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rho-associated coiled-coil-containing protein kinase 1; p160ROCK; ROK-beta; Rho-associated protein kinase 1 (ROCK1)

Function: (also see pathology below) - protein serine/threonine kinase - autophosphorylated on Ser & Thr - phosphorylated upon DNA damage, probably by ATM or ATR - regulates assembly of actin cytoskeleton, smooth muscle contraction, stress fiber & focal adhesion formation, neurite retraction, cell adhesion & motility via phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, PFN1 & PPP1R12A. - may regulate cell migration & invasiveness of tumor cells - phosphorylates FHOD1 & acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing - phosphorylates JIP3 & regulates the recruitment of JNK to JIP3 upon UVB-induced stress - acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation & stability - acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation - required for centrosome positioning & centrosome-dependent exit from mitosis - plays a role in terminal erythroid differentiation - may regulate closure of the eyelids & ventral body wall by inducing the assembly of actomyosin bundles - promotes keratinocyte terminal differentiation - role in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization - cleavage by caspase 3 induces phosphorylation of myosin light chain & apoptotic membrane blebbing - required for centromere positioning & centromere-dependent exit from mitosis - binds RHOA activated by GTP binding - activated by RHOA binding via conformation change - links Rho GTPases to Lim kinase 2 [4] - binds ADD1, GEM, RHOB, RHOC, myosin light chain & VIM - binds RHOE, PPP1R12A (MYPT1/MBS), LIMK1 & LIMK2 Inhibition: inhibited by Y-27632 Structure: - belongs to the Ser/Thr protein kinase family - contains 1 PH domain - contains 1 phorbol-ester/DAG-type zinc finger - contains 1 protein kinase domain - contains 1 REM (Hr1) repeat - C-terminal auto-inhibitory domain interferes with kinase activity - truncated ROCK1 is constitutively activated Compartment: - cytoplasm, centrosome, centriole - Golgi membrane, peripheral membrane - cell projection, lamellipodium, ruffle - colocalizes with ITGB1BP1 & ITGB1 at the cell membrane predominantly in lamellipodia & membrane ruffles, but also in retraction fibers - associated with mother centriole & intercentriolar linker - small proportion is associated with Golgi membranes Expression: detected in blood platelets, brain? Pathology: - inhibition of ROCK1 a) inhibits long-term memory [3] b) increases APP alpha-secretase activity [6] - calorie restriction induces SIRT1, which in turn, inhibits ROCK1 expression [6] - ROCK1 inhibits SIRT1 expression [6] 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* [7] * not clear if this is ROCK1, ROCK2 or both [7] Genetics: - a segmental duplication of chromosome 18 involving ROCK1 & USP14 is one of the few features distinguishing the human genome from the chimpanzee genome. [3,5]

Interactions

molecular events

Related

ROCK1 (rho-associated coiled-coil-containing protein kinase) gene

General

evolutionary divergent human protein rho-associated kinase ROCK zinc finger protein

Properties

SIZE: MW = 158 kD entity length = 1354 aa COMPARTMENT: cytoplasm golgi MOTIF: acetylation site SITE: N-TERMINUS EFFECTOR-BOUND: acetyl kinase domain SITE: 76-338 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 82-90 ATP-binding site NAME: ATP-binding site SITE: 105-105 aspartate residue {D198} AGC-kinase C-terminal {341-409} coiled coil {422-612} S/T phosphorylation site glutamate-rich region {636-980} MOTIF: glutamate residue (SEVERAL) RhoA binding {998-1010} coiled coil {1011-1102} proteolytic site {1113-1114} auto-inhibitory {1115-1354} MOTIF: PH domain {1118-1317} Zinc finger NAME: Zinc finger SITE: 1228-1281 EFFECTOR-BOUND: Zn+2 STATE: active state

Database Correlations

OMIM 601702 UniProt Q13464 PFAM correlations Entrez Gene 6093 ENZYME 2.7.1.37

References

  1. Coleman ML et al Membrane blebbing during apoptosis results from caspase- mediated activation of ROCK I. Nature Cell Biology 3:339-345, 2001 PMID: 11283606
  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. Fortna A, Kim Y, MacLaren E, Marshall K, Hahn G, Meltesen L, Brenton M, Hink R, Burgers S, Hernandez-Boussard T, Karimpour- Fard A, Glueck D, McGavran L, Berry R, Pollack J, Sikela JM. Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biol. 2004 Jul;2(7):E207. Epub 2004 Jul 13. PMID: 15252450
  4. Vardouli L, Moustakas A, Stournaras C. LIM-kinase 2 and cofilin phosphorylation mediate actin cytoskeleton reorganization induced by transforming growth factor-beta. J Biol Chem. 2005 Mar 25;280(12):11448-57. Epub 2005 Jan 11. PMID: 15647284
  5. Goidts V, Szamalek JM, Hameister H, Kehrer-Sawatzki H. Segmental duplication associated with the human-specific inversion of chromosome 18: a further example of the impact of segmental duplications on karyotype and genome evolution in primates. Hum Genet. 2004 Jul;115(2):116-22. Epub 2004 May 7. PMID: 15133654
  6. Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem. 2006 Aug 4;281(31):21745-54. Epub 2006 Jun 2. PMID: 16751189
  7. 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