ROCK*

Protein ROCK*

Identifiers
Rho associated coiled-coil containing protein kinase 1
HUGO:ROCK1 hgnc_id:HGNC:10251 HGNC:10251 ENTREZ:6093 UNIPROT:Q13464
Rho associated coiled-coil containing protein kinase 2
HUGO:ROCK2 hgnc_id:HGNC:10252 HGNC:10252 ENTREZ:9475 UNIPROT:O75116
HUGO:ROCK1 HUGO:ROCK2
ROCK
HUGO:ROCK1, HGNC:10251, ENTREZ:6093, UNIPROT:Q13464, GENECARDS:GC18M018529
HUGO:ROCK2, HGNC:10252, ENTREZ:9475, UNIPROT:O75116, GENECARDS:GC02M011272
HUGO:ROCK1 HGNC:10251 ENTREZ:6093 UNIPROT:Q13464 GENECARDS:ROCK1 REACTOME:153167 KEGG:6093 ATLASONC:GC_ROCK1 WIKI:ROCK1
HUGO:ROCK2 HGNC:10252 ENTREZ:9475 UNIPROT:O75116 GENECARDS:ROCK2 REACTOME:153173 KEGG:9475 ATLASONC:ROCK2ID43474ch2p25 WIKI:ROCK2

Maps_Modules
HMC:TUMOR_PROMOTING_INFLAMMATION
HMC:ACTIVATING_INVASION_AND_METASTASIS
Cancer Associated Fibroblasts / MOTILITY
EMT Senescence / EMT_REGULATORS
EMT Senescence / CYTOSKELETON_POLARITY
EMT Senescence / SENESCENCE
HMC:EVADING_GROWTH_SUPPRESSORS
Survival / WNT_NON_CANONICAL

References
CASCADE:LIF
CASCADE:TGFB
PMID:18037882
Rho???ROCK function is required in leading fibroblasts probably downstream of integrins a5b1 and a3b1
Actomyosin contractility in CAFs, as in many other cell types, results from phosphorylation of MLC2 in myosin II downstream of the Rho kinases ROCK I and II
PMID:21840487
ROCK acts together with JAK1, in regulation of actomyosin contractility treatment with ROCK inhibitors reduced phosphorylation of STAT3 in CAFs
ROCK-induced STAT3 phosphorylation required JAK kinase activity
PMID:10953004
ROCK not only inhibits myosin phosphatase but also phosphorylates MLC directly in the center of cells (fibroblasts). At the cell periphery, on the other hand, MLCK but not ROCK appears to be the kinase responsible for phosphorylating MLC. These results suggest that ROCK and MLCK play distinct roles in spatial regulation of MLC phosphorylation.
PMID:24857661
Long-term stimulation of both TGF-?? and LIF cytokines also upregulated RhoA small GTPase and myosin light chain 2 (MLC2) proteins, leading to an increase in MLC2 phosphorylation at ser19, which attests for an increased activity (Figure S2D). Finally, forced expression of an active form of ROCK (ROCK-ER) (Croft and Olson, 2006) following 4-hydroxytamoxifen (4OHT) treatment was sufficient to induce hDF contractility (Figure S2E), proinvasive capacity (Figures S2Fa and b), and MLC2 phosphorylation (Figure S2G) and also rescued the inhibitory effect of P6 or anti-LIF antibody treatments under TGF-??1 stimulation
Rho???ROCK function is required only in stromal fibroblasts for collective SCC invasion
PMID:12778124
In the inactive form, the pleckstrin homology (PH) domain and the Rho-binding domain (RBD) of ROCK bind to the amino-terminal region of the protein, which forms an autoinhibitory loop.
Activated, GTP-bound Rho binds to the RBD of ROCK, which results in an open conformation of the kinase and frees the catalytic activity.

ROCK*|active|open@Cytosol

References
em_emtc_emtc_re470:( EMT Senescence ) PMID:22154077, PMID:17522712
em_emtc_emtc_re472( EMT Senescence ):
PMID:22154077, PMID:17522712
CDC42 promotes changes in actin cytoskeleton by several pathways.
PMID:10461188
PMID:11950587
PMID:11340065
PMID:10559936
PMID:10613909
PMID:11413130
CDC42 activates PAK1,2,3,4 and CDC42BPA (MRCKalpha) which phosphorylate LIMK1,2.
LIMK1,2 subsquently phosphorylate and inhibit Cofilin
Destrin as actin depolymerizing factor, once phosphorylated by LIMK1,2 is inactive and thus this phosphorylation leads to actin polymerization and stimulation of filopodia and stress fibers formation.
PMID:11018042
LIMK1 is regulated by Pak1,
em_emtc_emtc_re708( EMT Senescence ):
PMID:9287351
ERM family (ezrin/radixin/moesin)
Direct interaction of the ARHGDI family with ERM family initiates the activation of the Rho small G protein.
PMID:10047517
Regulation of cortical structure by the ERM protein family.
PMID:12045227
Rho-dependent and -independent activation mechanisms of ERM proteins: an essential role for polyphosphoinositides in vivo.
ERM proteins crosslink actin filaments to plasma membranes and are involved in the organization of the cortical cytoskeleton, especially in the formation of microvilli.
ERM proteins are reported to be activated as crosslinkers in a Rho-dependent manner and are stabilized when phosphorylated at their C-terminal threonine residue to create C-terminal threonine- phosphorylated ERM proteins
However, ERM proteins appear to be activated in the absence of Rho activation and remain active without C-terminal phosphorylation.
Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) affected the activation of ERM proteins regardless of cell type.
The Rho-independent activation mechanism of ERM proteins therefore exists.
Both Rho-dependent and -independent activation of ERM proteins require a local elevation of PtdIns(4,5)P2 concentration in vivo.
PMID:7579708
Cell extracts contain ezrin dimers and ezrin-moesin heterodimers in addition to monomers.
Dimerization in vivo requires an activation step that exposes this masked domain.
The conformationally inaccessible C-terminal region included the F-actin binding site, suggesting that this activity is likewise regulated by masking.
PMID:8527459
Ezrin, a membrane-microfilament linking protein, exists largely as a monomeric protein in solution.
Purified ezrin monomers normally have a masked C-terminal domain (termed a C-ERMAD) that, upon exposure, can associate with an N-terminal domain (termed N-ERMAD) of another ezrin molecule.
Purified ezrin dimers also have masked C-ERMADs.
Since radixin and moesin, the two other members of the closely related ERM protein family, both contain N- and C-ERMADs, the results we have documented and models proposed for ezrin are likely to apply to radixin and moesin as well
PMID:12802084
ERM proteins exist in the cytoplasm as dormant monomers in which the F-actin cytoskeleton and the plasma membrane binding sites are masked.
This closed conformation is due to an intramolecular N- to C-ERM association domain (ERMAD) interaction.
Abrogation of the N and C-ERMAD interaction is required to open up the molecules and to expose their cryptic binding sites
2 factors have been implicated in the activation of ERM proteins:
-The binding to phosphatidylinositol 4,5-biphosphate is required for their interaction with actin in vitro and with membrane proteins in vivo
-Phosphorylation of a conserved threonine residue in the C-ERMAD, T567, inhibits the N and C-ERMAD interaction in vitro and in vivo, converts inactive oligomers to active monomers
PMID:8522586
PMID:10970850
Phosphorylation of ezrin by the Rho kinase ROCK is required for Rho-induced focal adhesion assembly.

ROCK*|closed@Nucleus

References
em_emtc_emtc_re470:( EMT Senescence ) PMID:22154077, PMID:17522712
em_emtc_emtc_re698( EMT Senescence ):
PMID:12778124
In the inactive form, the pleckstrin homology (PH) domain and the Rho-binding domain (RBD) of ROCK bind to the amino-terminal region of the protein, which forms an autoinhibitory loop.
Activated, GTP-bound Rho binds to the RBD of ROCK, which results in an open conformation of the kinase and frees the catalytic activity.

Modifications:
In compartment: Cytoplasm

ROCK*@Cytoplasm

In compartment: Cytosol

ROCK*@Cytosol
ROCK*|active|open@Cytosol

In compartment: Nucleus

ROCK*|closed@Nucleus

Participates in complexes:
In compartment: Cytoplasm

RHOA:ROCK*@Cytoplasm

Participates in reactions:
As Reactant or Product:

As Catalyser: