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Rho-associated protein kinase 2; Rho kinase 2; Rho-associated, coiled-coil-containing protein kinase 2; p164 ROCK-2 (ROCK2, KIAA0619)

Function: - regulates assembly of actin cytoskeleton & cell polarity - role in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber & focal adhesion formation, neurite retraction, cell adhesion & cell motility - phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A & VIM - phosphorylates SORL1 & IRF4 - negative regulator of VEGF-induced angiogenic endothelial cell activation - positively regulates the activation of p42/MAPK1-p44/MAPK3 & of p90RSK/RPS6KA1 during myogenic differentiation. - role in initiation of centrosome duplication - inhibits keratinocyte terminal differentiation - may regulate closure of the eyelids & ventral body wall through organization of actomyosin bundles - role in the regulation of synaptic spines in hippocampus - role in generating the circadian rhythm of aortic myofilament Ca+2 sensitivity & vascular contractility by modulating the myosin ight chain phosphorylation - phosphorylated upon DNA damage, probably by ATM or ATR - activated by RHOA binding - binds RHOA that has been activated by GTP binding - phosphorylation at Tyr-722 reduces its binding to RHOA & is crucial for focal adhesion dynamics - dephosphorylation by PTPN11 stimulates its RHOA binding activity - cleaved by granzyme B during apoptosis, leading to constitutive activation of the kinase & membrane blebbing - interacts with CHORDC1, RAF1, PPP1R12A, SORL1, EP300 & BRCA2 - interacts with NPM1 - binds IRS1, RHOB & RHOC - not cleaved by caspase 3 - inhibited by Y-27632 Cofactor: Mg+2 (putative) Structure: - homodimer - belongs to the protein kinase superfamily, AGC Ser/Thr protein kinase family - contains 1 AGC-kinase C-terminal domain - contains 1 PH domain - contains 1 phorbol-ester/DAG-type Zn+2 finger - contains 1 protein kinase domain - contains 1 REM (Hr1) repeat - interaction between Thr-414 & Asp-48 is essential for kinase activity & dimerization - unlike ROCK1, does not contain caspase 3 consensus sequence in C-terminal Compartment: - cytoplasm (putative) - cell membrane - nucleus. cytoplasm, cytoskeleton, microtubule organizing center, centrosome - cytoplasmic, & associated with actin microfilaments & the plasma membrane Comparative biology: - IL-17 facilitates Rho-kinase dependent inhibitory phosphorylation of endothelial nitric oxide synthase in mice reducing nitric oxide production in cerebral endothelial cells, inhibiting resting cerebral perfusion & endothelial function, leading to cognitive impairment* [5] * not clear if this is ROCK1, ROCK2 or both [5]

General

phosphoprotein rho-associated kinase ROCK zinc finger protein

Properties

SIZE: entity length = 1388 aa MW = 161 kD COMPARTMENT: cytoplasm STATE: active state MOTIF: kinase domain SITE: 92-354 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 98-106 ATP-binding site NAME: ATP-binding site SITE: 121-121 aspartate residue {D214} AGC-kinase C-terminal {357-425} MOTIF: Ser phosphorylation site {S425} coiled coil {429-1024} MOTIF: REM {475-559} RHOA binding {979-1047} coiled coil {1053-1131} MOTIF: Thr phosphorylation site {T1078} Ser phosphorylation site {S1133} Ser phosphorylation site {S1134} Ser phosphorylation site {S1137} PH domain {1150-1349} MOTIF: Zinc finger NAME: Zinc finger SITE: 1260-1315 EFFECTOR-BOUND: Zn+2 Ser phosphorylation site {S1362} Ser phosphorylation site {S1374}

Database Correlations

OMIM 604002 UniProt O75116 PFAM correlations Entrez Gene 9475 Kegg hsa:9475 ENZYME 2.7.11.1

References

  1. UniProt :accession O75116
  2. Sebbagh M et al Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nature Cell Biology 3:346-52, 2001 PMID: 11283607
  3. PubMed links - PMID: 699075 - PMID: 17015463 - PMID: 015463 - PMID: 19997641 - PMID: 997641 - PMID: 21147781
  4. Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/ROCK2ID43474ch2p25.html
  5. Faraco G, Brea D, Garcia-Bonilla L. Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nature Neuroscience. Jan 15, 2018 PMID: 29335605 https://www.nature.com/articles/s41593-017-0059-z