Full text data of ROCK2
ROCK2
(KIAA0619)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Rho-associated protein kinase 2; 2.7.11.1 (Rho kinase 2; Rho-associated, coiled-coil-containing protein kinase 2; Rho-associated, coiled-coil-containing protein kinase II; ROCK-II; p164 ROCK-2)
Rho-associated protein kinase 2; 2.7.11.1 (Rho kinase 2; Rho-associated, coiled-coil-containing protein kinase 2; Rho-associated, coiled-coil-containing protein kinase II; ROCK-II; p164 ROCK-2)
UniProt
O75116
ID ROCK2_HUMAN Reviewed; 1388 AA.
AC O75116; Q53QZ0; Q53SJ7; Q9UQN5;
DT 24-MAY-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 24-NOV-2009, sequence version 4.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Rho-associated protein kinase 2;
DE EC=2.7.11.1;
DE AltName: Full=Rho kinase 2;
DE AltName: Full=Rho-associated, coiled-coil-containing protein kinase 2;
DE AltName: Full=Rho-associated, coiled-coil-containing protein kinase II;
DE Short=ROCK-II;
DE AltName: Full=p164 ROCK-2;
GN Name=ROCK2; Synonyms=KIAA0619;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ASN-431.
RC TISSUE=Brain;
RX PubMed=9933571; DOI=10.1006/geno.1998.5344;
RA Takahashi N., Tuiki H., Saya H., Kaibuchi K.;
RT "Localization of the gene coding for ROCK II/Rho kinase on human
RT chromosome 2p24.";
RL Genomics 55:235-237(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASN-431.
RC TISSUE=Brain;
RX PubMed=9734811; DOI=10.1093/dnares/5.3.169;
RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H.,
RA Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. X.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 5:169-176(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
RP FUNCTION, AND INTERACTION WITH PPP1R12A.
RX PubMed=10579722; DOI=10.1083/jcb.147.5.1023;
RA Kawano Y., Fukata Y., Oshiro N., Amano M., Nakamura T., Ito M.,
RA Matsumura F., Inagaki M., Kaibuchi K.;
RT "Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase
RT by Rho-kinase in vivo.";
RL J. Cell Biol. 147:1023-1038(1999).
RN [5]
RP CLEAVAGE BY GRANZYME B, MUTAGENESIS OF ASP-1131, AND FUNCTION.
RX PubMed=15699075; DOI=10.1084/jem.20031877;
RA Sebbagh M., Hamelin J., Bertoglio J., Solary E., Breard J.;
RT "Direct cleavage of ROCK II by granzyme B induces target cell membrane
RT blebbing in a caspase-independent manner.";
RL J. Exp. Med. 201:465-471(2005).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH EP300.
RX PubMed=16574662; DOI=10.1074/jbc.M510954200;
RA Tanaka T., Nishimura D., Wu R.C., Amano M., Iso T., Kedes L.,
RA Nishida H., Kaibuchi K., Hamamori Y.;
RT "Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase.";
RL J. Biol. Chem. 281:15320-15329(2006).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH NPM1.
RX PubMed=17015463; DOI=10.1128/MCB.01383-06;
RA Ma Z., Kanai M., Kawamura K., Kaibuchi K., Ye K., Fukasawa K.;
RT "Interaction between ROCK II and nucleophosmin/B23 in the regulation
RT of centrosome duplication.";
RL Mol. Cell. Biol. 26:9016-9034(2006).
RN [8]
RP PHOSPHORYLATION AT TYR-722, AND DEPHOSPHORYLATION.
RX PubMed=18559669; DOI=10.1083/jcb.200710187;
RA Lee H.H., Chang Z.F.;
RT "Regulation of RhoA-dependent ROCKII activation by Shp2.";
RL J. Cell Biol. 181:999-1012(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1137, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1137, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP FUNCTION, AND INTERACTION WITH PPP1R12A.
RX PubMed=19131646; DOI=10.1161/CIRCRESAHA.108.188524;
RA Wang Y., Zheng X.R., Riddick N., Bryden M., Baur W., Zhang X.,
RA Surks H.K.;
RT "ROCK isoform regulation of myosin phosphatase and contractility in
RT vascular smooth muscle cells.";
RL Circ. Res. 104:531-540(2009).
RN [12]
RP FUNCTION.
RX PubMed=19997641; DOI=10.1371/journal.pone.0008190;
RA Lock F.E., Hotchin N.A.;
RT "Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte
RT differentiation.";
RL PLoS ONE 4:E8190-E8190(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1137, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [14]
RP INTERACTION WITH CHORDC1.
RX PubMed=20230755; DOI=10.1016/j.devcel.2009.12.020;
RA Ferretti R., Palumbo V., Di Savino A., Velasco S., Sbroggio M.,
RA Sportoletti P., Micale L., Turco E., Silengo L., Palumbo G.,
RA Hirsch E., Teruya-Feldstein J., Bonaccorsi S., Pandolfi P.P.,
RA Gatti M., Tarone G., Brancaccio M.;
RT "Morgana/chp-1, a ROCK inhibitor involved in centrosome duplication
RT and tumorigenesis.";
RL Dev. Cell 18:486-495(2010).
RN [15]
RP PHOSPHORYLATION AT TYR-722.
RX PubMed=20826462; DOI=10.1242/jcs.071555;
RA Lee H.H., Tien S.C., Jou T.S., Chang Y.C., Jhong J.G., Chang Z.F.;
RT "Src-dependent phosphorylation of ROCK participates in regulation of
RT focal adhesion dynamics.";
RL J. Cell Sci. 123:3368-3377(2010).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1137, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP FUNCTION, AND INTERACTION WITH BRCA2.
RX PubMed=21084279; DOI=10.1158/0008-5472.CAN-10-0030;
RA Wang H.F., Takenaka K., Nakanishi A., Miki Y.;
RT "BRCA2 and nucleophosmin coregulate centrosome amplification and form
RT a complex with the Rho effector kinase ROCK2.";
RL Cancer Res. 71:68-77(2011).
RN [19]
RP FUNCTION, AND INTERACTION WITH SORL1.
RX PubMed=21147781; DOI=10.1074/jbc.M110.167239;
RA Herskowitz J.H., Seyfried N.T., Gearing M., Kahn R.A., Peng J.,
RA Levey A.I., Lah J.J.;
RT "Rho kinase II phosphorylation of the lipoprotein receptor LR11/SORLA
RT alters amyloid-beta production.";
RL J. Biol. Chem. 286:6117-6127(2011).
RN [20]
RP REVIEW.
RX PubMed=12778124; DOI=10.1038/nrm1128;
RA Riento K., Ridley A.J.;
RT "Rocks: multifunctional kinases in cell behaviour.";
RL Nat. Rev. Mol. Cell Biol. 4:446-456(2003).
RN [21]
RP REVIEW.
RX PubMed=20803696; DOI=10.1002/cm.20472;
RA Amano M., Nakayama M., Kaibuchi K.;
RT "Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell
RT polarity.";
RL Cytoskeleton 67:545-554(2010).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1137, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [23]
RP VARIANTS [LARGE SCALE ANALYSIS] ASN-431; VAL-601 AND PRO-1194.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Protein kinase which is a key regulator of actin
CC cytoskeleton and cell polarity. Involved in regulation of smooth
CC muscle contraction, actin cytoskeleton organization, stress fiber
CC and focal adhesion formation, neurite retraction, cell adhesion
CC and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR,
CC DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM.
CC Phosphorylates SORL1 and IRF4. Acts as a negative regulator of
CC VEGF-induced angiogenic endothelial cell activation. Positively
CC regulates the activation of p42/MAPK1-p44/MAPK3 and of
CC p90RSK/RPS6KA1 during myogenic differentiation. Plays an important
CC role in the timely initiation of centrosome duplication. Inhibits
CC keratinocyte terminal differentiation. May regulate closure of the
CC eyelids and ventral body wall through organization of actomyosin
CC bundles. Plays a critical role in the regulation of spine and
CC synaptic properties in the hippocampus.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium (By similarity).
CC -!- ENZYME REGULATION: Activated by RHOA binding. Inhibited by Y-27632
CC (By similarity).
CC -!- SUBUNIT: Homodimer. Interacts with IRS1, RHOB and RHOC (By
CC similarity). Interacts with RHOA (activated by GTP), PPP1R12A,
CC CHORDC1, SORL1, EP300 and BRCA2. Interacts with NPM1 and this
CC interaction enhances its activity. Interacts with RAF1 (By
CC similarity).
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane; Peripheral
CC membrane protein (By similarity). Nucleus. Cytoplasm,
CC cytoskeleton, microtubule organizing center, centrosome.
CC Note=Cytoplasmic, and associated with actin microfilaments and the
CC plasma membrane (By similarity).
CC -!- DOMAIN: An interaction between Thr-414 and Asp-48 is essential for
CC kinase activity and dimerization (By similarity).
CC -!- PTM: Phosphorylation at Tyr-722 reduces its binding to RHOA and is
CC crucial for focal adhesion dynamics. Dephosphorylation by PTPN11
CC stimulates its RHOA binding activity.
CC -!- PTM: Cleaved by granzyme B during apoptosis. This leads to
CC constitutive activation of the kinase and membrane blebbing.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family.
CC -!- SIMILARITY: Contains 1 AGC-kinase C-terminal domain.
CC -!- SIMILARITY: Contains 1 PH domain.
CC -!- SIMILARITY: Contains 1 phorbol-ester/DAG-type zinc finger.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 1 REM (Hr1) repeat.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAX93049.1; Type=Erroneous gene model prediction;
CC Sequence=BAA31594.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/ROCK2ID43474ch2p25.html";
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DR EMBL; D87931; BAA75636.1; -; mRNA.
DR EMBL; AB014519; BAA31594.2; ALT_INIT; mRNA.
DR EMBL; AC018463; AAX93049.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AC099344; AAY14825.1; -; Genomic_DNA.
DR RefSeq; NP_004841.2; NM_004850.3.
DR UniGene; Hs.681743; -.
DR PDB; 4L6Q; X-ray; 2.79 A; A/B=19-417.
DR PDBsum; 4L6Q; -.
DR ProteinModelPortal; O75116; -.
DR SMR; O75116; 27-417, 559-709, 979-1045, 1151-1351.
DR IntAct; O75116; 8.
DR MINT; MINT-4299744; -.
DR STRING; 9606.ENSP00000317985; -.
DR ChEMBL; CHEMBL2111459; -.
DR GuidetoPHARMACOLOGY; 1504; -.
DR PhosphoSite; O75116; -.
DR PaxDb; O75116; -.
DR PRIDE; O75116; -.
DR Ensembl; ENST00000315872; ENSP00000317985; ENSG00000134318.
DR GeneID; 9475; -.
DR KEGG; hsa:9475; -.
DR UCSC; uc002rbd.1; human.
DR CTD; 9475; -.
DR GeneCards; GC02M011272; -.
DR H-InvDB; HIX0001828; -.
DR HGNC; HGNC:10252; ROCK2.
DR HPA; CAB008666; -.
DR HPA; HPA007459; -.
DR MIM; 604002; gene.
DR neXtProt; NX_O75116; -.
DR PharmGKB; PA34624; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000017259; -.
DR HOVERGEN; HBG053111; -.
DR KO; K17388; -.
DR OMA; NQSIRRP; -.
DR OrthoDB; EOG7DZ8J4; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; O75116; -.
DR GenomeRNAi; 9475; -.
DR NextBio; 35508; -.
DR PRO; PR:O75116; -.
DR ArrayExpress; O75116; -.
DR Bgee; O75116; -.
DR CleanEx; HS_ROCK2; -.
DR Genevestigator; O75116; -.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031616; C:spindle pole centrosome; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; NAS:ProtInc.
DR GO; GO:0030036; P:actin cytoskeleton organization; IEA:Ensembl.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0051298; P:centrosome duplication; IMP:UniProtKB.
DR GO; GO:0000910; P:cytokinesis; NAS:ProtInc.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IMP:UniProtKB.
DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
DR GO; GO:0010825; P:positive regulation of centrosome duplication; IEA:Ensembl.
DR GO; GO:2000145; P:regulation of cell motility; TAS:UniProtKB.
DR GO; GO:2000114; P:regulation of establishment of cell polarity; TAS:UniProtKB.
DR GO; GO:0051893; P:regulation of focal adhesion assembly; TAS:UniProtKB.
DR GO; GO:0045616; P:regulation of keratinocyte differentiation; IMP:UniProtKB.
DR GO; GO:0051492; P:regulation of stress fiber assembly; TAS:UniProtKB.
DR GO; GO:0006939; P:smooth muscle contraction; TAS:UniProtKB.
DR Gene3D; 2.30.29.30; -; 2.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR011072; HR1_rho-bd.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR001849; Pleckstrin_homology.
DR InterPro; IPR002219; Prot_Kinase_C-like_PE/DAG-bd.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR020684; Rho-assoc_coiled-coil_kin.
DR InterPro; IPR015008; Rho-bd_dom.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR22988:SF3; PTHR22988:SF3; 1.
DR Pfam; PF02185; HR1; 1.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF08912; Rho_Binding; 1.
DR PIRSF; PIRSF037568; Rho_kinase; 1.
DR SMART; SM00109; C1; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS00479; ZF_DAG_PE_1; FALSE_NEG.
DR PROSITE; PS50081; ZF_DAG_PE_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Cell membrane; Coiled coil;
KW Complete proteome; Cytoplasm; Cytoskeleton; Kinase; Magnesium;
KW Membrane; Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Zinc; Zinc-finger.
FT CHAIN 1 1388 Rho-associated protein kinase 2.
FT /FTId=PRO_0000086625.
FT DOMAIN 92 354 Protein kinase.
FT DOMAIN 357 425 AGC-kinase C-terminal.
FT REPEAT 475 559 REM.
FT DOMAIN 1150 1349 PH.
FT NP_BIND 98 106 ATP (By similarity).
FT ZN_FING 1260 1315 Phorbol-ester/DAG-type.
FT REGION 363 784 Interaction with PPP1R12A.
FT REGION 373 420 Interaction with NPM1.
FT REGION 979 1047 RHOA binding (By similarity).
FT COILED 429 1024 Potential.
FT COILED 1053 1131 Potential.
FT ACT_SITE 214 214 Proton acceptor (By similarity).
FT BINDING 121 121 ATP (By similarity).
FT SITE 1131 1132 Cleavage; by granzyme B.
FT MOD_RES 414 414 Phosphothreonine; by ROCK2 (By
FT similarity).
FT MOD_RES 722 722 Phosphotyrosine; by SRC.
FT MOD_RES 1137 1137 Phosphoserine.
FT VARIANT 431 431 T -> N (in dbSNP:rs2230774).
FT /FTId=VAR_041062.
FT VARIANT 601 601 D -> V (in dbSNP:rs35768389).
FT /FTId=VAR_041063.
FT VARIANT 1083 1083 K -> M (in dbSNP:rs34945852).
FT /FTId=VAR_057110.
FT VARIANT 1194 1194 S -> P (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_041064.
FT MUTAGEN 1131 1131 D->A: Abolishes cleavage by granzyme B.
FT CONFLICT 83 83 R -> K (in Ref. 1; BAA75636).
FT HELIX 29 35
FT HELIX 43 57
FT HELIX 60 63
FT HELIX 66 85
FT HELIX 89 91
FT STRAND 92 100
FT STRAND 102 111
FT TURN 112 114
FT STRAND 117 124
FT HELIX 125 130
FT HELIX 138 146
FT STRAND 155 160
FT STRAND 162 169
FT HELIX 177 183
FT HELIX 188 207
FT HELIX 217 219
FT STRAND 220 222
FT STRAND 228 230
FT STRAND 241 246
FT HELIX 254 256
FT HELIX 259 264
FT STRAND 270 272
FT HELIX 274 289
FT HELIX 299 307
FT HELIX 309 312
FT HELIX 323 332
FT HELIX 336 338
FT TURN 340 343
FT HELIX 346 349
FT HELIX 352 354
FT TURN 361 363
FT HELIX 364 366
FT HELIX 408 410
SQ SEQUENCE 1388 AA; 160900 MW; 876240F410C2487E CRC64;
MSRPPPTGKM PGAPETAPGD GAGASRQRKL EALIRDPRSP INVESLLDGL NSLVLDLDFP
ALRKNKNIDN FLNRYEKIVK KIRGLQMKAE DYDVVKVIGR GAFGEVQLVR HKASQKVYAM
KLLSKFEMIK RSDSAFFWEE RDIMAFANSP WVVQLFYAFQ DDRYLYMVME YMPGGDLVNL
MSNYDVPEKW AKFYTAEVVL ALDAIHSMGL IHRDVKPDNM LLDKHGHLKL ADFGTCMKMD
ETGMVHCDTA VGTPDYISPE VLKSQGGDGF YGRECDWWSV GVFLYEMLVG DTPFYADSLV
GTYSKIMDHK NSLCFPEDAE ISKHAKNLIC AFLTDREVRL GRNGVEEIRQ HPFFKNDQWH
WDNIRETAAP VVPELSSDID SSNFDDIEDD KGDVETFPIP KAFVGNQLPF IGFTYYRENL
LLSDSPSCRE TDSIQSRKNE ESQEIQKKLY TLEEHLSNEM QAKEELEQKC KSVNTRLEKT
AKELEEEITL RKSVESALRQ LEREKALLQH KNAEYQRKAD HEADKKRNLE NDVNSLKDQL
EDLKKRNQNS QISTEKVNQL QRQLDETNAL LRTESDTAAR LRKTQAESSK QIQQLESNNR
DLQDKNCLLE TAKLKLEKEF INLQSALESE RRDRTHGSEI INDLQGRICG LEEDLKNGKI
LLAKVELEKR QLQERFTDLE KEKSNMEIDM TYQLKVIQQS LEQEEAEHKA TKARLADKNK
IYESIEEAKS EAMKEMEKKL LEERTLKQKV ENLLLEAEKR CSLLDCDLKQ SQQKINELLK
QKDVLNEDVR NLTLKIEQET QKRCLTQNDL KMQTQQVNTL KMSEKQLKQE NNHLMEMKMN
LEKQNAELRK ERQDADGQMK ELQDQLEAEQ YFSTLYKTQV RELKEECEEK TKLGKELQQK
KQELQDERDS LAAQLEITLT KADSEQLARS IAEEQYSDLE KEKIMKELEI KEMMARHKQE
LTEKDATIAS LEETNRTLTS DVANLANEKE ELNNKLKDVQ EQLSRLKDEE ISAAAIKAQF
EKQLLTERTL KTQAVNKLAE IMNRKEPVKR GNDTDVRRKE KENRKLHMEL KSEREKLTQQ
MIKYQKELNE MQAQIAEESQ IRIELQMTLD SKDSDIEQLR SQLQALHIGL DSSSIGSGPG
DAEADDGFPE SRLEGWLSLP VRNNTKKFGW VKKYVIVSSK KILFYDSEQD KEQSNPYMVL
DIDKLFHVRP VTQTDVYRAD AKEIPRIFQI LYANEGESKK EQEFPVEPVG EKSNYICHKG
HEFIPTLYHF PTNCEACMKP LWHMFKPPPA LECRRCHIKC HKDHMDKKEE IIAPCKVYYD
ISTAKNLLLL ANSTEEQQKW VSRLVKKIPK KPPAPDPFAR SSPRTSMKIQ QNQSIRRPSR
QLAPNKPS
//
ID ROCK2_HUMAN Reviewed; 1388 AA.
AC O75116; Q53QZ0; Q53SJ7; Q9UQN5;
DT 24-MAY-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 24-NOV-2009, sequence version 4.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Rho-associated protein kinase 2;
DE EC=2.7.11.1;
DE AltName: Full=Rho kinase 2;
DE AltName: Full=Rho-associated, coiled-coil-containing protein kinase 2;
DE AltName: Full=Rho-associated, coiled-coil-containing protein kinase II;
DE Short=ROCK-II;
DE AltName: Full=p164 ROCK-2;
GN Name=ROCK2; Synonyms=KIAA0619;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ASN-431.
RC TISSUE=Brain;
RX PubMed=9933571; DOI=10.1006/geno.1998.5344;
RA Takahashi N., Tuiki H., Saya H., Kaibuchi K.;
RT "Localization of the gene coding for ROCK II/Rho kinase on human
RT chromosome 2p24.";
RL Genomics 55:235-237(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASN-431.
RC TISSUE=Brain;
RX PubMed=9734811; DOI=10.1093/dnares/5.3.169;
RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H.,
RA Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. X.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 5:169-176(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
RP FUNCTION, AND INTERACTION WITH PPP1R12A.
RX PubMed=10579722; DOI=10.1083/jcb.147.5.1023;
RA Kawano Y., Fukata Y., Oshiro N., Amano M., Nakamura T., Ito M.,
RA Matsumura F., Inagaki M., Kaibuchi K.;
RT "Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase
RT by Rho-kinase in vivo.";
RL J. Cell Biol. 147:1023-1038(1999).
RN [5]
RP CLEAVAGE BY GRANZYME B, MUTAGENESIS OF ASP-1131, AND FUNCTION.
RX PubMed=15699075; DOI=10.1084/jem.20031877;
RA Sebbagh M., Hamelin J., Bertoglio J., Solary E., Breard J.;
RT "Direct cleavage of ROCK II by granzyme B induces target cell membrane
RT blebbing in a caspase-independent manner.";
RL J. Exp. Med. 201:465-471(2005).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH EP300.
RX PubMed=16574662; DOI=10.1074/jbc.M510954200;
RA Tanaka T., Nishimura D., Wu R.C., Amano M., Iso T., Kedes L.,
RA Nishida H., Kaibuchi K., Hamamori Y.;
RT "Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase.";
RL J. Biol. Chem. 281:15320-15329(2006).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH NPM1.
RX PubMed=17015463; DOI=10.1128/MCB.01383-06;
RA Ma Z., Kanai M., Kawamura K., Kaibuchi K., Ye K., Fukasawa K.;
RT "Interaction between ROCK II and nucleophosmin/B23 in the regulation
RT of centrosome duplication.";
RL Mol. Cell. Biol. 26:9016-9034(2006).
RN [8]
RP PHOSPHORYLATION AT TYR-722, AND DEPHOSPHORYLATION.
RX PubMed=18559669; DOI=10.1083/jcb.200710187;
RA Lee H.H., Chang Z.F.;
RT "Regulation of RhoA-dependent ROCKII activation by Shp2.";
RL J. Cell Biol. 181:999-1012(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1137, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1137, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP FUNCTION, AND INTERACTION WITH PPP1R12A.
RX PubMed=19131646; DOI=10.1161/CIRCRESAHA.108.188524;
RA Wang Y., Zheng X.R., Riddick N., Bryden M., Baur W., Zhang X.,
RA Surks H.K.;
RT "ROCK isoform regulation of myosin phosphatase and contractility in
RT vascular smooth muscle cells.";
RL Circ. Res. 104:531-540(2009).
RN [12]
RP FUNCTION.
RX PubMed=19997641; DOI=10.1371/journal.pone.0008190;
RA Lock F.E., Hotchin N.A.;
RT "Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte
RT differentiation.";
RL PLoS ONE 4:E8190-E8190(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1137, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [14]
RP INTERACTION WITH CHORDC1.
RX PubMed=20230755; DOI=10.1016/j.devcel.2009.12.020;
RA Ferretti R., Palumbo V., Di Savino A., Velasco S., Sbroggio M.,
RA Sportoletti P., Micale L., Turco E., Silengo L., Palumbo G.,
RA Hirsch E., Teruya-Feldstein J., Bonaccorsi S., Pandolfi P.P.,
RA Gatti M., Tarone G., Brancaccio M.;
RT "Morgana/chp-1, a ROCK inhibitor involved in centrosome duplication
RT and tumorigenesis.";
RL Dev. Cell 18:486-495(2010).
RN [15]
RP PHOSPHORYLATION AT TYR-722.
RX PubMed=20826462; DOI=10.1242/jcs.071555;
RA Lee H.H., Tien S.C., Jou T.S., Chang Y.C., Jhong J.G., Chang Z.F.;
RT "Src-dependent phosphorylation of ROCK participates in regulation of
RT focal adhesion dynamics.";
RL J. Cell Sci. 123:3368-3377(2010).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1137, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP FUNCTION, AND INTERACTION WITH BRCA2.
RX PubMed=21084279; DOI=10.1158/0008-5472.CAN-10-0030;
RA Wang H.F., Takenaka K., Nakanishi A., Miki Y.;
RT "BRCA2 and nucleophosmin coregulate centrosome amplification and form
RT a complex with the Rho effector kinase ROCK2.";
RL Cancer Res. 71:68-77(2011).
RN [19]
RP FUNCTION, AND INTERACTION WITH SORL1.
RX PubMed=21147781; DOI=10.1074/jbc.M110.167239;
RA Herskowitz J.H., Seyfried N.T., Gearing M., Kahn R.A., Peng J.,
RA Levey A.I., Lah J.J.;
RT "Rho kinase II phosphorylation of the lipoprotein receptor LR11/SORLA
RT alters amyloid-beta production.";
RL J. Biol. Chem. 286:6117-6127(2011).
RN [20]
RP REVIEW.
RX PubMed=12778124; DOI=10.1038/nrm1128;
RA Riento K., Ridley A.J.;
RT "Rocks: multifunctional kinases in cell behaviour.";
RL Nat. Rev. Mol. Cell Biol. 4:446-456(2003).
RN [21]
RP REVIEW.
RX PubMed=20803696; DOI=10.1002/cm.20472;
RA Amano M., Nakayama M., Kaibuchi K.;
RT "Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell
RT polarity.";
RL Cytoskeleton 67:545-554(2010).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1137, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [23]
RP VARIANTS [LARGE SCALE ANALYSIS] ASN-431; VAL-601 AND PRO-1194.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Protein kinase which is a key regulator of actin
CC cytoskeleton and cell polarity. Involved in regulation of smooth
CC muscle contraction, actin cytoskeleton organization, stress fiber
CC and focal adhesion formation, neurite retraction, cell adhesion
CC and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR,
CC DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM.
CC Phosphorylates SORL1 and IRF4. Acts as a negative regulator of
CC VEGF-induced angiogenic endothelial cell activation. Positively
CC regulates the activation of p42/MAPK1-p44/MAPK3 and of
CC p90RSK/RPS6KA1 during myogenic differentiation. Plays an important
CC role in the timely initiation of centrosome duplication. Inhibits
CC keratinocyte terminal differentiation. May regulate closure of the
CC eyelids and ventral body wall through organization of actomyosin
CC bundles. Plays a critical role in the regulation of spine and
CC synaptic properties in the hippocampus.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium (By similarity).
CC -!- ENZYME REGULATION: Activated by RHOA binding. Inhibited by Y-27632
CC (By similarity).
CC -!- SUBUNIT: Homodimer. Interacts with IRS1, RHOB and RHOC (By
CC similarity). Interacts with RHOA (activated by GTP), PPP1R12A,
CC CHORDC1, SORL1, EP300 and BRCA2. Interacts with NPM1 and this
CC interaction enhances its activity. Interacts with RAF1 (By
CC similarity).
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane; Peripheral
CC membrane protein (By similarity). Nucleus. Cytoplasm,
CC cytoskeleton, microtubule organizing center, centrosome.
CC Note=Cytoplasmic, and associated with actin microfilaments and the
CC plasma membrane (By similarity).
CC -!- DOMAIN: An interaction between Thr-414 and Asp-48 is essential for
CC kinase activity and dimerization (By similarity).
CC -!- PTM: Phosphorylation at Tyr-722 reduces its binding to RHOA and is
CC crucial for focal adhesion dynamics. Dephosphorylation by PTPN11
CC stimulates its RHOA binding activity.
CC -!- PTM: Cleaved by granzyme B during apoptosis. This leads to
CC constitutive activation of the kinase and membrane blebbing.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family.
CC -!- SIMILARITY: Contains 1 AGC-kinase C-terminal domain.
CC -!- SIMILARITY: Contains 1 PH domain.
CC -!- SIMILARITY: Contains 1 phorbol-ester/DAG-type zinc finger.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 1 REM (Hr1) repeat.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAX93049.1; Type=Erroneous gene model prediction;
CC Sequence=BAA31594.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/ROCK2ID43474ch2p25.html";
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DR EMBL; D87931; BAA75636.1; -; mRNA.
DR EMBL; AB014519; BAA31594.2; ALT_INIT; mRNA.
DR EMBL; AC018463; AAX93049.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AC099344; AAY14825.1; -; Genomic_DNA.
DR RefSeq; NP_004841.2; NM_004850.3.
DR UniGene; Hs.681743; -.
DR PDB; 4L6Q; X-ray; 2.79 A; A/B=19-417.
DR PDBsum; 4L6Q; -.
DR ProteinModelPortal; O75116; -.
DR SMR; O75116; 27-417, 559-709, 979-1045, 1151-1351.
DR IntAct; O75116; 8.
DR MINT; MINT-4299744; -.
DR STRING; 9606.ENSP00000317985; -.
DR ChEMBL; CHEMBL2111459; -.
DR GuidetoPHARMACOLOGY; 1504; -.
DR PhosphoSite; O75116; -.
DR PaxDb; O75116; -.
DR PRIDE; O75116; -.
DR Ensembl; ENST00000315872; ENSP00000317985; ENSG00000134318.
DR GeneID; 9475; -.
DR KEGG; hsa:9475; -.
DR UCSC; uc002rbd.1; human.
DR CTD; 9475; -.
DR GeneCards; GC02M011272; -.
DR H-InvDB; HIX0001828; -.
DR HGNC; HGNC:10252; ROCK2.
DR HPA; CAB008666; -.
DR HPA; HPA007459; -.
DR MIM; 604002; gene.
DR neXtProt; NX_O75116; -.
DR PharmGKB; PA34624; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000017259; -.
DR HOVERGEN; HBG053111; -.
DR KO; K17388; -.
DR OMA; NQSIRRP; -.
DR OrthoDB; EOG7DZ8J4; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; O75116; -.
DR GenomeRNAi; 9475; -.
DR NextBio; 35508; -.
DR PRO; PR:O75116; -.
DR ArrayExpress; O75116; -.
DR Bgee; O75116; -.
DR CleanEx; HS_ROCK2; -.
DR Genevestigator; O75116; -.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031616; C:spindle pole centrosome; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; NAS:ProtInc.
DR GO; GO:0030036; P:actin cytoskeleton organization; IEA:Ensembl.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0051298; P:centrosome duplication; IMP:UniProtKB.
DR GO; GO:0000910; P:cytokinesis; NAS:ProtInc.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IMP:UniProtKB.
DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
DR GO; GO:0010825; P:positive regulation of centrosome duplication; IEA:Ensembl.
DR GO; GO:2000145; P:regulation of cell motility; TAS:UniProtKB.
DR GO; GO:2000114; P:regulation of establishment of cell polarity; TAS:UniProtKB.
DR GO; GO:0051893; P:regulation of focal adhesion assembly; TAS:UniProtKB.
DR GO; GO:0045616; P:regulation of keratinocyte differentiation; IMP:UniProtKB.
DR GO; GO:0051492; P:regulation of stress fiber assembly; TAS:UniProtKB.
DR GO; GO:0006939; P:smooth muscle contraction; TAS:UniProtKB.
DR Gene3D; 2.30.29.30; -; 2.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR011072; HR1_rho-bd.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR001849; Pleckstrin_homology.
DR InterPro; IPR002219; Prot_Kinase_C-like_PE/DAG-bd.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR020684; Rho-assoc_coiled-coil_kin.
DR InterPro; IPR015008; Rho-bd_dom.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR22988:SF3; PTHR22988:SF3; 1.
DR Pfam; PF02185; HR1; 1.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF08912; Rho_Binding; 1.
DR PIRSF; PIRSF037568; Rho_kinase; 1.
DR SMART; SM00109; C1; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS00479; ZF_DAG_PE_1; FALSE_NEG.
DR PROSITE; PS50081; ZF_DAG_PE_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Cell membrane; Coiled coil;
KW Complete proteome; Cytoplasm; Cytoskeleton; Kinase; Magnesium;
KW Membrane; Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Zinc; Zinc-finger.
FT CHAIN 1 1388 Rho-associated protein kinase 2.
FT /FTId=PRO_0000086625.
FT DOMAIN 92 354 Protein kinase.
FT DOMAIN 357 425 AGC-kinase C-terminal.
FT REPEAT 475 559 REM.
FT DOMAIN 1150 1349 PH.
FT NP_BIND 98 106 ATP (By similarity).
FT ZN_FING 1260 1315 Phorbol-ester/DAG-type.
FT REGION 363 784 Interaction with PPP1R12A.
FT REGION 373 420 Interaction with NPM1.
FT REGION 979 1047 RHOA binding (By similarity).
FT COILED 429 1024 Potential.
FT COILED 1053 1131 Potential.
FT ACT_SITE 214 214 Proton acceptor (By similarity).
FT BINDING 121 121 ATP (By similarity).
FT SITE 1131 1132 Cleavage; by granzyme B.
FT MOD_RES 414 414 Phosphothreonine; by ROCK2 (By
FT similarity).
FT MOD_RES 722 722 Phosphotyrosine; by SRC.
FT MOD_RES 1137 1137 Phosphoserine.
FT VARIANT 431 431 T -> N (in dbSNP:rs2230774).
FT /FTId=VAR_041062.
FT VARIANT 601 601 D -> V (in dbSNP:rs35768389).
FT /FTId=VAR_041063.
FT VARIANT 1083 1083 K -> M (in dbSNP:rs34945852).
FT /FTId=VAR_057110.
FT VARIANT 1194 1194 S -> P (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_041064.
FT MUTAGEN 1131 1131 D->A: Abolishes cleavage by granzyme B.
FT CONFLICT 83 83 R -> K (in Ref. 1; BAA75636).
FT HELIX 29 35
FT HELIX 43 57
FT HELIX 60 63
FT HELIX 66 85
FT HELIX 89 91
FT STRAND 92 100
FT STRAND 102 111
FT TURN 112 114
FT STRAND 117 124
FT HELIX 125 130
FT HELIX 138 146
FT STRAND 155 160
FT STRAND 162 169
FT HELIX 177 183
FT HELIX 188 207
FT HELIX 217 219
FT STRAND 220 222
FT STRAND 228 230
FT STRAND 241 246
FT HELIX 254 256
FT HELIX 259 264
FT STRAND 270 272
FT HELIX 274 289
FT HELIX 299 307
FT HELIX 309 312
FT HELIX 323 332
FT HELIX 336 338
FT TURN 340 343
FT HELIX 346 349
FT HELIX 352 354
FT TURN 361 363
FT HELIX 364 366
FT HELIX 408 410
SQ SEQUENCE 1388 AA; 160900 MW; 876240F410C2487E CRC64;
MSRPPPTGKM PGAPETAPGD GAGASRQRKL EALIRDPRSP INVESLLDGL NSLVLDLDFP
ALRKNKNIDN FLNRYEKIVK KIRGLQMKAE DYDVVKVIGR GAFGEVQLVR HKASQKVYAM
KLLSKFEMIK RSDSAFFWEE RDIMAFANSP WVVQLFYAFQ DDRYLYMVME YMPGGDLVNL
MSNYDVPEKW AKFYTAEVVL ALDAIHSMGL IHRDVKPDNM LLDKHGHLKL ADFGTCMKMD
ETGMVHCDTA VGTPDYISPE VLKSQGGDGF YGRECDWWSV GVFLYEMLVG DTPFYADSLV
GTYSKIMDHK NSLCFPEDAE ISKHAKNLIC AFLTDREVRL GRNGVEEIRQ HPFFKNDQWH
WDNIRETAAP VVPELSSDID SSNFDDIEDD KGDVETFPIP KAFVGNQLPF IGFTYYRENL
LLSDSPSCRE TDSIQSRKNE ESQEIQKKLY TLEEHLSNEM QAKEELEQKC KSVNTRLEKT
AKELEEEITL RKSVESALRQ LEREKALLQH KNAEYQRKAD HEADKKRNLE NDVNSLKDQL
EDLKKRNQNS QISTEKVNQL QRQLDETNAL LRTESDTAAR LRKTQAESSK QIQQLESNNR
DLQDKNCLLE TAKLKLEKEF INLQSALESE RRDRTHGSEI INDLQGRICG LEEDLKNGKI
LLAKVELEKR QLQERFTDLE KEKSNMEIDM TYQLKVIQQS LEQEEAEHKA TKARLADKNK
IYESIEEAKS EAMKEMEKKL LEERTLKQKV ENLLLEAEKR CSLLDCDLKQ SQQKINELLK
QKDVLNEDVR NLTLKIEQET QKRCLTQNDL KMQTQQVNTL KMSEKQLKQE NNHLMEMKMN
LEKQNAELRK ERQDADGQMK ELQDQLEAEQ YFSTLYKTQV RELKEECEEK TKLGKELQQK
KQELQDERDS LAAQLEITLT KADSEQLARS IAEEQYSDLE KEKIMKELEI KEMMARHKQE
LTEKDATIAS LEETNRTLTS DVANLANEKE ELNNKLKDVQ EQLSRLKDEE ISAAAIKAQF
EKQLLTERTL KTQAVNKLAE IMNRKEPVKR GNDTDVRRKE KENRKLHMEL KSEREKLTQQ
MIKYQKELNE MQAQIAEESQ IRIELQMTLD SKDSDIEQLR SQLQALHIGL DSSSIGSGPG
DAEADDGFPE SRLEGWLSLP VRNNTKKFGW VKKYVIVSSK KILFYDSEQD KEQSNPYMVL
DIDKLFHVRP VTQTDVYRAD AKEIPRIFQI LYANEGESKK EQEFPVEPVG EKSNYICHKG
HEFIPTLYHF PTNCEACMKP LWHMFKPPPA LECRRCHIKC HKDHMDKKEE IIAPCKVYYD
ISTAKNLLLL ANSTEEQQKW VSRLVKKIPK KPPAPDPFAR SSPRTSMKIQ QNQSIRRPSR
QLAPNKPS
//
MIM
604002
*RECORD*
*FIELD* NO
604002
*FIELD* TI
*604002 RHO-ASSOCIATED COILED-COIL-CONTAINING PROTEIN KINASE 2; ROCK2
*FIELD* TX
DESCRIPTION
read more
ROCK2 is a serine/threonine kinase that regulates cytokinesis, smooth
muscle contraction, the formation of actin stress fibers and focal
adhesions, and the activation of the c-fos (164810) serum response
element. ROCK2, which is an isozyme of ROCK1 (601702), is a target for
the small GTPase Rho (e.g., 165390).
CLONING
By screening human brain cDNAs for the potential to encode proteins
larger than 50 kD, Ishikawa et al. (1998) identified a ROCK2 cDNA, which
they called KIAA0619. RT-PCR detected ROCK2 expression in all human
tissues examined.
By PCR of human cDNA using oligonucleotides based on the sequence of a
bovine ROCK2 cDNA, followed by screening of a human brain cDNA library,
Takahashi et al. (1999) isolated a human ROCK2 cDNA. The deduced
1,388-amino acid human ROCK2 protein is 97% and 96% identical to bovine
ROCK2 and mouse Rock2, respectively.
GENE FUNCTION
Nakamura et al. (2001) studied the role of Rho in the migration of
corneal epithelial cells in rabbit. They detected both ROCK1 and ROCK2
in the corneal epithelium at protein and mRNA levels. They found that
exoenzyme C3, a Rho inhibitor, inhibits corneal epithelial migration in
a dose-dependent manner and prevents the stimulatory effect of the Rho
activator lysophosphatidic acid (LPA). Both cytochalasin B, an inhibitor
of actin filament assembly, and ML7, an inhibitor of myosin light chain
kinase, also prevent LPA stimulation of epithelial migration. The
authors suggested that Rho mediates corneal epithelial migration in
response to external stimuli by regulating the organization of the actin
cytoskeleton.
Rao et al. (2001) investigated the role of Rho kinase in the modulation
of aqueous humor outflow facility. The treatment of human trabecular
meshwork and canal of Schlemm cells with a Rho kinase-specific inhibitor
led to significant but reversible changes in cell shape and decreased
actin stress fibers, focal adhesions, and protein phosphotyrosine
staining. Based on the Rho kinase inhibitor-induced changes in myosin
light chain phosphorylation and actomyosin organization, the authors
suggested that cellular relaxation and loss of cell-substratum adhesions
in the human trabecular meshwork and canal of Schlemm cells could result
in either increased paracellular fluid flow across the canal of Schlemm
or altered flow pathway through the juxtacanalicular tissue, thereby
lowering resistance to outflow. They suggested Rho kinase as a potential
target for the development of drugs to modulate intraocular pressure in
glaucoma patients.
MAPPING
Ishikawa et al. (1998) mapped the ROCK2 gene to chromosome 2 using a
radiation hybrid mapping panel. By FISH and radiation hybrid mapping,
Takahashi et al. (1999) localized the ROCK2 gene to 2p24.
MOLECULAR GENETICS
- Role in Left-Right Patterning
By high-resolution genotyping of 262 heterotaxy (see HTX1, 306955)
subjects and 991 controls, Fakhro et al. (2011) identified a 2-fold
excess of subjects with rare genic copy number variations (CNVs) in
heterotaxy (14.5% vs 7.4%, p = 1.5 x 10(-4)). Although 7 of 45
heterotaxy CNVs were large chromosomal abnormalities, 38 smaller CNVs
altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ
hybridization identified 7 of these 22 genes with expression in the
ciliated left-right organizer, a marked enrichment compared with 40 of
845 previously studied genes (7-fold enrichment, p less than 10(-6)).
Morpholino knockdown in Xenopus of heterotaxy candidate genes
demonstrated that 5 genes (NEK2, 604043; ROCK2; TGFBR2, 190182; GALNT11,
615130; and NUP188, 615587) strongly disrupted both morphologic
left-right development and expression of PITX2 (601542), a molecular
marker of left-right patterning. These effects were specific, because 0
of 13 control genes from rare heterotaxy or control CNVs produced
significant left-right abnormalities (p = 0.001).
ANIMAL MODEL
Thumkeo et al. (2003) found that about 90% of Rock2-null embryos died
after 13.5 days postcoitum. Surviving mutant mice of both genders were
born runts, subsequently developed without gross abnormality, and were
fertile. Whole-mount staining for a knocked-in reporter gene revealed
that Rock2 was highly expressed in the labyrinth layer of the placenta.
Disruption of architecture and extensive thrombus formation were found
in the labyrinth layer of Rock2-null mice. While no obvious alterations
in the actin filament structures were found in the labyrinth layer of
Rock2-null placenta, and stress fibers were formed in cultured
Rock2-null trophoblasts, there was elevated expression of plasminogen
activator inhibitor-1 (173360) in Rock2-null placenta. Thumkeo et al.
(2003) concluded that Rock2 is essential in inhibiting blood coagulation
and maintaining blood flow in the endothelium-free labyrinth layer and
that loss of Rock2 leads to thrombus formation, placental dysfunction,
intrauterine growth retardation, and fetal death.
*FIELD* RF
1. Fakhro, K. A.; Choi, M.; Ware, S. M.; Belmont, J. W.; Towbin, J.
A.; Lifton, R. P.; Khokha, M. K.; Brueckner, M.: Rare copy number
variations in congenital heart disease patients identify unique genes
in left-right patterning. Proc. Nat. Acad. Sci. 108: 2915-2920,
2011.
2. Ishikawa, K.; Nagase, T.; Suyama, M.; Miyajima, N.; Tanaka, A.;
Kotani, H.; Nomura, N.; Ohara, O.: Prediction of the coding sequences
of unidentified human genes. X. The complete sequences of 100 new
cDNA clones from brain which can code for large proteins in vitro. DNA
Res. 5: 169-176, 1998.
3. Nakamura, M.; Nagano, T.; Chikama, T.; Nishida, T.: Role of the
small GTP-binding protein Rho in epithelial cell migration in the
rabbit cornea. Invest. Ophthal. Vis. Sci. 42: 941-947, 2001.
4. Rao, P. V.; Deng, P.-F.; Kumar, J.; Epstein, D. L.: Modulation
of aqueous humor outflow facility by the Rho kinase-specific inhibitor
Y-27632. Invest. Ophthal. Vis. Sci. 42: 1029-1037, 2001. Note: Erratum:
Invest. Ophthal. Vis. Sci. 42: 1690 only, 2001.
5. Takahashi, N.; Tuiki, H.; Saya, H.; Kaibuchi, K.: Localization
of the gene coding for ROCK II/Rho kinase on human chromosome 2p24. Genomics 55:
235-237, 1999.
6. Thumkeo, D.; Keel, J.; Ishizaki, T.; Hirose, M.; Nonomura, K.;
Oshima, H.; Oshima, M.; Taketo, M. M.; Narumiya, S.: Targeted disruption
of the mouse Rho-associated kinase 2 gene results in intrauterine
growth retardation and fetal death. Molec. Cell. Biol. 23: 5043-5055,
2003.
*FIELD* CN
Ada Hamosh - updated: 01/16/2014
Patricia A. Hartz - updated: 10/27/2003
Patti M. Sherman - updated: 8/27/1999
*FIELD* CD
Patti M. Sherman: 7/9/1999
*FIELD* ED
alopez: 01/16/2014
terry: 8/8/2012
alopez: 6/25/2009
cwells: 10/31/2003
terry: 10/27/2003
mcapotos: 6/21/2001
mcapotos: 6/20/2001
mgross: 8/30/1999
psherman: 8/27/1999
mgross: 7/28/1999
psherman: 7/26/1999
*RECORD*
*FIELD* NO
604002
*FIELD* TI
*604002 RHO-ASSOCIATED COILED-COIL-CONTAINING PROTEIN KINASE 2; ROCK2
*FIELD* TX
DESCRIPTION
read more
ROCK2 is a serine/threonine kinase that regulates cytokinesis, smooth
muscle contraction, the formation of actin stress fibers and focal
adhesions, and the activation of the c-fos (164810) serum response
element. ROCK2, which is an isozyme of ROCK1 (601702), is a target for
the small GTPase Rho (e.g., 165390).
CLONING
By screening human brain cDNAs for the potential to encode proteins
larger than 50 kD, Ishikawa et al. (1998) identified a ROCK2 cDNA, which
they called KIAA0619. RT-PCR detected ROCK2 expression in all human
tissues examined.
By PCR of human cDNA using oligonucleotides based on the sequence of a
bovine ROCK2 cDNA, followed by screening of a human brain cDNA library,
Takahashi et al. (1999) isolated a human ROCK2 cDNA. The deduced
1,388-amino acid human ROCK2 protein is 97% and 96% identical to bovine
ROCK2 and mouse Rock2, respectively.
GENE FUNCTION
Nakamura et al. (2001) studied the role of Rho in the migration of
corneal epithelial cells in rabbit. They detected both ROCK1 and ROCK2
in the corneal epithelium at protein and mRNA levels. They found that
exoenzyme C3, a Rho inhibitor, inhibits corneal epithelial migration in
a dose-dependent manner and prevents the stimulatory effect of the Rho
activator lysophosphatidic acid (LPA). Both cytochalasin B, an inhibitor
of actin filament assembly, and ML7, an inhibitor of myosin light chain
kinase, also prevent LPA stimulation of epithelial migration. The
authors suggested that Rho mediates corneal epithelial migration in
response to external stimuli by regulating the organization of the actin
cytoskeleton.
Rao et al. (2001) investigated the role of Rho kinase in the modulation
of aqueous humor outflow facility. The treatment of human trabecular
meshwork and canal of Schlemm cells with a Rho kinase-specific inhibitor
led to significant but reversible changes in cell shape and decreased
actin stress fibers, focal adhesions, and protein phosphotyrosine
staining. Based on the Rho kinase inhibitor-induced changes in myosin
light chain phosphorylation and actomyosin organization, the authors
suggested that cellular relaxation and loss of cell-substratum adhesions
in the human trabecular meshwork and canal of Schlemm cells could result
in either increased paracellular fluid flow across the canal of Schlemm
or altered flow pathway through the juxtacanalicular tissue, thereby
lowering resistance to outflow. They suggested Rho kinase as a potential
target for the development of drugs to modulate intraocular pressure in
glaucoma patients.
MAPPING
Ishikawa et al. (1998) mapped the ROCK2 gene to chromosome 2 using a
radiation hybrid mapping panel. By FISH and radiation hybrid mapping,
Takahashi et al. (1999) localized the ROCK2 gene to 2p24.
MOLECULAR GENETICS
- Role in Left-Right Patterning
By high-resolution genotyping of 262 heterotaxy (see HTX1, 306955)
subjects and 991 controls, Fakhro et al. (2011) identified a 2-fold
excess of subjects with rare genic copy number variations (CNVs) in
heterotaxy (14.5% vs 7.4%, p = 1.5 x 10(-4)). Although 7 of 45
heterotaxy CNVs were large chromosomal abnormalities, 38 smaller CNVs
altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ
hybridization identified 7 of these 22 genes with expression in the
ciliated left-right organizer, a marked enrichment compared with 40 of
845 previously studied genes (7-fold enrichment, p less than 10(-6)).
Morpholino knockdown in Xenopus of heterotaxy candidate genes
demonstrated that 5 genes (NEK2, 604043; ROCK2; TGFBR2, 190182; GALNT11,
615130; and NUP188, 615587) strongly disrupted both morphologic
left-right development and expression of PITX2 (601542), a molecular
marker of left-right patterning. These effects were specific, because 0
of 13 control genes from rare heterotaxy or control CNVs produced
significant left-right abnormalities (p = 0.001).
ANIMAL MODEL
Thumkeo et al. (2003) found that about 90% of Rock2-null embryos died
after 13.5 days postcoitum. Surviving mutant mice of both genders were
born runts, subsequently developed without gross abnormality, and were
fertile. Whole-mount staining for a knocked-in reporter gene revealed
that Rock2 was highly expressed in the labyrinth layer of the placenta.
Disruption of architecture and extensive thrombus formation were found
in the labyrinth layer of Rock2-null mice. While no obvious alterations
in the actin filament structures were found in the labyrinth layer of
Rock2-null placenta, and stress fibers were formed in cultured
Rock2-null trophoblasts, there was elevated expression of plasminogen
activator inhibitor-1 (173360) in Rock2-null placenta. Thumkeo et al.
(2003) concluded that Rock2 is essential in inhibiting blood coagulation
and maintaining blood flow in the endothelium-free labyrinth layer and
that loss of Rock2 leads to thrombus formation, placental dysfunction,
intrauterine growth retardation, and fetal death.
*FIELD* RF
1. Fakhro, K. A.; Choi, M.; Ware, S. M.; Belmont, J. W.; Towbin, J.
A.; Lifton, R. P.; Khokha, M. K.; Brueckner, M.: Rare copy number
variations in congenital heart disease patients identify unique genes
in left-right patterning. Proc. Nat. Acad. Sci. 108: 2915-2920,
2011.
2. Ishikawa, K.; Nagase, T.; Suyama, M.; Miyajima, N.; Tanaka, A.;
Kotani, H.; Nomura, N.; Ohara, O.: Prediction of the coding sequences
of unidentified human genes. X. The complete sequences of 100 new
cDNA clones from brain which can code for large proteins in vitro. DNA
Res. 5: 169-176, 1998.
3. Nakamura, M.; Nagano, T.; Chikama, T.; Nishida, T.: Role of the
small GTP-binding protein Rho in epithelial cell migration in the
rabbit cornea. Invest. Ophthal. Vis. Sci. 42: 941-947, 2001.
4. Rao, P. V.; Deng, P.-F.; Kumar, J.; Epstein, D. L.: Modulation
of aqueous humor outflow facility by the Rho kinase-specific inhibitor
Y-27632. Invest. Ophthal. Vis. Sci. 42: 1029-1037, 2001. Note: Erratum:
Invest. Ophthal. Vis. Sci. 42: 1690 only, 2001.
5. Takahashi, N.; Tuiki, H.; Saya, H.; Kaibuchi, K.: Localization
of the gene coding for ROCK II/Rho kinase on human chromosome 2p24. Genomics 55:
235-237, 1999.
6. Thumkeo, D.; Keel, J.; Ishizaki, T.; Hirose, M.; Nonomura, K.;
Oshima, H.; Oshima, M.; Taketo, M. M.; Narumiya, S.: Targeted disruption
of the mouse Rho-associated kinase 2 gene results in intrauterine
growth retardation and fetal death. Molec. Cell. Biol. 23: 5043-5055,
2003.
*FIELD* CN
Ada Hamosh - updated: 01/16/2014
Patricia A. Hartz - updated: 10/27/2003
Patti M. Sherman - updated: 8/27/1999
*FIELD* CD
Patti M. Sherman: 7/9/1999
*FIELD* ED
alopez: 01/16/2014
terry: 8/8/2012
alopez: 6/25/2009
cwells: 10/31/2003
terry: 10/27/2003
mcapotos: 6/21/2001
mcapotos: 6/20/2001
mgross: 8/30/1999
psherman: 8/27/1999
mgross: 7/28/1999
psherman: 7/26/1999