Search results for ROCK1

Showing 19 results out of 30

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Protein (6 results from a total of 6)

Identifier: R-HSA-212509
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: ROCK1: Q13464
Identifier: R-HSA-6804967
Species: Homo sapiens
Compartment: secretory granule lumen
Primary external reference: UniProt: ROCK1: Q13464
Identifier: R-HSA-6806527
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: Q13464
Identifier: R-HSA-4687777
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: ROCK1: Q13464
Identifier: R-HSA-212523
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: Q13464
Identifier: R-HSA-212524
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: Q13464

Reaction (6 results from a total of 17)

Identifier: R-NUL-421733
Species: Homo sapiens, Rattus norvegicus
Compartment: cytosol
ROCK-mediated phosphorylation of LIM kinase 2 at threonine residue T505 was demonstrated in experiments that used recombinant rat Limk2 and recombinant human ROCK2 ( Sumi et al. 2001).
Identifier: R-HSA-5228992
Species: Homo sapiens
Compartment: cytosol
RHOA propagates downstream signals by binding to effector proteins such as Rho-associated, coiled-coil containing protein kinases (ROCKs). ROCKs consist of an amino-terminal kinase domain, followed by a Rho-binding domain (RBD) and a carboxy terminal cysteine-rich domain (CRD) located within the pleckstrin homology (PH) motif. RHOA:GTP interacts with the RBD domain and activates the phosphotransferase activity (Ishizaki et al. 1996, Amano et al. 2000).
Identifier: R-HSA-3928647
Species: Homo sapiens
Compartment: plasma membrane, cytosol
RHOA propagates downstream signals by binding to effector proteins such as Rho-associated, coiled-coil containing protein kinases (ROCKs). ROCKs consist of an amino-terminal kinase domain, followed by a Rho-binding domain (RBD) and a carboxy terminal cysteine-rich domain (CRD) located within the pleckstrin homology (PH) motif. RHOA:GTP interacts with the RBD domain and activates the phosphotransferase activity (Ishizaki et al. 1996, Amano et al. 2000).
Identifier: R-HSA-5218826
Species: Homo sapiens
Compartment: cytosol, plasma membrane
Activated ROCK directly phosphorylates FAK1 on S732. This phosphorylation induces a conformational change that is necessary to trigger the phosphorylation of FAK on Y407 (Le Bouef et al. 2006).
Identifier: R-HSA-9680443
Species: Homo sapiens
Compartment: cytosol
Ripasudil (Glanatec), as its hydrochloride hydrate (K-115), is a specifc Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor (ROCKi) used for the treatment of glaucoma and ocular hypertension in Japan (Garnock-Jones 2014). Netarsudil is a USA-approved ROCKi used to treat glaucoma and ocular hypertenstion (Sturdivant et al. 2016, Tanna & Johnson 2018).
Identifier: R-HSA-1912416
Species: Homo sapiens
Compartment: nucleoplasm
NOTCH1 was cloned as a chromosome 9 gene involved in translocation t(7;9)(q34;q34.3) in several T-cell acute lymphoblastic leukemia (T-ALL) patients. The gene was found to be highly homologous to the Drosophila gene Notch and was initially named TAN-1 (translocation-associated Notch homolog). Transcripts of NOTCH1 were detected in many fetal and adult human and mouse tissues, with the highest abundance in lymphoid tissues. The translocation t(7;9)(q34;q34.3) found in a small fraction of T-ALL patients puts NOTCH1 transcription under the control of the T-cell receptor-beta (TCRB) locus, which results in expression of truncated peptides that lack the extracellular ligand binding domain and are constitutively active (reviewed by Grabher et al. 2006). Activating NOTCH1 point mutations, mainly affecting the extracellular heterodimerization domain and/or the C-terminal PEST domain, are found in more than 50% of human T-ALLs (Weng et al. 2004).

Studies of mouse Rbpj knockout embryos and zebrafish Mib (mindbomb) mutants indicate that the NOTCH1 coactivator complex positively regulates NOTCH1 transcription. The RBPJ-binding site(s) that the NOTCH1 coactivator complex normally binds have not been found in the NOTCH1 promoter, however, so this effect may be indirect and its mechanism is unknown (Del Monte et al. 2007).

CCND1 (cyclin D1) forms a complex with CREBBP and binds to the NOTCH1 promoter, stimulating NOTCH1 transcription. The involvement of CCND1 in transcriptional regulation of NOTCH1 was established in mouse retinas and the rat retinal precursor cell line R28 (Bienvenu et al. 2010).

E2F1 and E2F3 are able to bind to the NOTCH1 promoter and activate NOTCH1 transcription (Viatour et al. 2011).

NOTCH1 promoter possesses two putative p53-binding sites. Chromatin immunoprecipitation (ChIP) assays of human primary keratinocytes showed binding of endogenous p53 protein to both sites. Experiments in which p53 was downregulated or overexpressed implicate p53 as a positive regulator of NOTCH1 expression in primary human keratinocytes. It is likely that p53-mediated regulation of NOTCH1 expression involves interplay with other cell-type specific determinants of gene expression (Lefort et al. 2007). In lymphoid cells, NOTCH1 expression may be negatively regulated by p53 (Laws and Osborne 2004). Other proteins implicated in the negative regulation of NOTCH1 transcription are KLF9 (Ying et al. 2011), JARID2 (Mysliwiec et al. 2011, Mysliwiec et al. 2012), KLF4 and SP3 (Lambertini et al. 2010), and p63 (Yugawa et al. 2010).

Set (2 results from a total of 2)

Identifier: R-HSA-419057
Species: Homo sapiens
Compartment: cytosol
ROCK I (alternatively called ROK ?) and ROCK II (also known as Rho kinase or ROK ?) were originally isolated as RhoA-GTP interacting proteins. The kinase domains of ROCK I and ROCK II are 92% identical, and so far there is no evidence that they phosphorylate different substrates. RhoA, RhoB, and RhoC associate with and activate ROCK but other GTP-binding proteins can be inhibitors, e.g. RhoE, Rad and Gem. PDK1 kinase promotes ROCK I activity not through phosphorylation but by blocking RhoE association. PLK1 can phosphorylate ROCK II and this enhances the effect of RhoA. Arachidonic acid can activate ROCK independently of Rho.
Identifier: R-HSA-4687776
Species: Homo sapiens
Compartment: cytosol
ROCK I (alternatively called ROK ?) and ROCK II (also known as Rho kinase or ROK ?) were originally isolated as RhoA-GTP interacting proteins. The kinase domains of ROCK I and ROCK II are 92% identical, and so far there is no evidence that they phosphorylate different substrates. RhoA, RhoB, and RhoC associate with and activate ROCK but other GTP-binding proteins can be inhibitors, e.g. RhoE, Rad and Gem. PDK1 kinase promotes ROCK I activity not through phosphorylation but by blocking RhoE association. PLK1 can phosphorylate ROCK II and this enhances the effect of RhoA. Arachidonic acid can activate ROCK independently of Rho.

Complex (2 results from a total of 2)

Identifier: R-HSA-9680444
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5228987
Species: Homo sapiens
Compartment: cytosol

Pathway (3 results from a total of 3)

Identifier: R-HSA-9696264
Species: Homo sapiens
RND3 (RHOE) is an atypical RHO GTPase from the RND subfamily. RND3 is constitutively bound to GTP and lacks GTPase activity. No guanine nucleotide exchange factors (GEFs), GTPase activator proteins (GAPs) or guanine nucleotide dissociation inhibitors (GDIs) act on RND3. RND3 is a direct antagonist of ROCK1 kinase activity. RND3 prevents phosphorylation of ROCK1 targets and, similar to RND1, induces stress fiber disassembly. RND3 regulates cell migration, establishment of neuronal polarity, heart development, and myometrium changes during pregnancy. Defective RND3 function is related to cardiomyopathy, hydrocephalus and cancer. Like RND1, RND3 is implicated both as a tumor suppressor and an oncogene in cancer, and can both increase and decrease sensitivity to chemotherapeutic agents, which depends on cancer type and stage. For review, please refer to Jie et al. 2015 and Paysan et al. 2016.
Identifier: R-HSA-5627117
Species: Homo sapiens
Compartment: plasma membrane
RHO associated, coiled-coil containing protein kinases ROCK1 and ROCK2 consist of a serine/threonine kinase domain, a coiled-coil region, a RHO-binding domain and a plekstrin homology (PH) domain interspersed with a cysteine-rich region. The PH domain inhibits the kinase activity of ROCKs by an intramolecular fold. ROCKs are activated by binding of the GTP-bound RHO GTPases RHOA, RHOB and RHOC to the RHO binding domain of ROCKs (Ishizaki et al. 1996, Leung et al. 1996), which disrupts the autoinhibitory fold. Once activated, ROCK1 and ROCK2 phosphorylate target proteins, many of which are involved in the stabilization of actin filaments and generation of actin-myosin contractile force. ROCKs phosphorylate LIM kinases LIMK1 and LIMK2, enabling LIMKs to phosphorylate cofilin, an actin depolymerizing factor, and thereby regulate the reorganization of the actin cytoskeleton (Ohashi et al. 2000, Sumi et al. 2001). ROCKs phosphorylate MRLC (myosin regulatory light chain), which stimulates the activity of non-muscle myosin II (NMM2), an actin-based motor protein involved in cell migration, polarity formation and cytokinesis (Amano et al. 1996, Riento and Ridley 2003, Watanabe et al. 2007, Amano et al. 2010). ROCKs also phosphorylate the myosin phosphatase targeting subunit (MYPT1) of MLC phosphatase, inhibiting the phosphatase activity and preventing dephosphorylation of MRLC. This pathway acts synergistically with phosphorylation of MRLC by ROCKs towards stimulation of non-muscle myosin II activity (Kimura et al. 1996, Amano et al. 2010).
Identifier: R-HSA-195258
Species: Homo sapiens
RHO GTPases regulate cell behaviour by activating a number of downstream effectors that regulate cytoskeletal organization, intracellular trafficking and transcription (reviewed by Sahai and Marshall 2002).

One of the best studied RHO GTPase effectors are protein kinases ROCK1 and ROCK2, which are activated by binding RHOA, RHOB or RHOC. ROCK1 and ROCK2 phosphorylate many proteins involved in the stabilization of actin filaments and generation of actin-myosin contractile force, such as LIM kinases and myosin regulatory light chains (MRLC) (Amano et al. 1996, Ishizaki et al. 1996, Leung et al. 1996, Ohashi et al. 2000, Sumi et al. 2001, Riento and Ridley 2003, Watanabe et al. 2007).

PAK1, PAK2 and PAK3, members of the p21-activated kinase family, are activated by binding to RHO GTPases RAC1 and CDC42 and subsequent autophosphorylation and are involved in cytoskeleton regulation (Manser et al. 1994, Manser et al. 1995, Zhang et al. 1998, Edwards et al. 1999, Lei et al. 2000, Parrini et al. 2002; reviewed by Daniels and Bokoch 1999, Szczepanowska 2009).

RHOA, RHOB, RHOC and RAC1 activate protein kinase C related kinases (PKNs) PKN1, PKN2 and PKN3 (Maesaki et al. 1999, Zong et al. 1999, Owen et al. 2003, Modha et al. 2008, Hutchinson et al. 2011, Hutchinson et al. 2013), bringing them in proximity to the PIP3-activated PDPK1 (PDK1) and thus enabling PDPK1-mediated phosphorylation of PKN1, PKN2 and PKN3 (Flynn et al. 2000, Torbett et al. 2003). PKNs play important roles in cytoskeleton organization (Hamaguchi et al. 2000), regulation of cell cycle (Misaki et al. 2001), receptor trafficking (Metzger et al. 2003) and apoptosis (Takahashi et al. 1998). PKN1 is also involved in the ligand-dependent transcriptional activation by the androgen receptor (Metzger et al. 2003, Metzger et al. 2005, Metzger et al. 2008).

Citron kinase (CIT) binds RHO GTPases RHOA, RHOB, RHOC and RAC1 (Madaule et al. 1995), but the mechanism of CIT activation by GTP-bound RHO GTPases has not been elucidated. CIT and RHOA are implicated to act together in Golgi apparatus organization through regulation of the actin cytoskeleton (Camera et al. 2003). CIT is also involved in the regulation of cytokinesis through its interaction with KIF14 (Gruneberg et al. 2006, Bassi et al. 2013, Watanabe et al. 2013).

RHOA, RHOG, RAC1 and CDC42 bind kinectin (KTN1), a kinesin anchor protein involved in kinesin-mediated vesicle motility (Vignal et al. 2001, Hotta et al. 1996). The effect of RHOG activity on cellular morphology, exhibited in the formation of microtubule-dependent cellular protrusions, depends both on RHOG interaction with KTN1, as well as on the kinesin activity (Vignal et al. 2001). RHOG and KTN1 also cooperate in microtubule-dependent lysosomal transport (Vignal et al. 2001).

IQGAP proteins IQGAP1, IQGAP2 and IQGAP3, bind RAC1 and CDC42 and stabilize them in their GTP-bound state (Kuroda et al. 1996, Swart-Mataraza et al. 2002, Wang et al. 2007). IQGAPs bind F-actin filaments and modulate cell shape and motility through regulation of G-actin/F-actin equilibrium (Brill et al. 1996, Fukata et al. 1997, Bashour et al. 1997, Wang et al. 2007, Pelikan-Conchaudron et al. 2011). Binding of IQGAPs to F-actin is inhibited by calmodulin (Bashour et al. 1997, Pelikan-Conchaudron et al. 2011). IQGAP1 is involved in the regulation of adherens junctions through its interaction with E-cadherin (CDH1) and catenins (CTTNB1 and CTTNA1) (Kuroda et al. 1998, Hage et al. 2009). IQGAP1 contributes to cell polarity and lamellipodia formation through its interaction with microtubules (Fukata et al. 2002, Suzuki and Takahashi 2008).

RHOQ (TC10) regulates the trafficking of CFTR (cystic fibrosis transmembrane conductance regulator) by binding to the Golgi-associated protein GOPC (also known as PIST, FIG and CAL). In the absence of RHOQ, GOPC bound to CFTR directs CFTR for lysosomal degradation, while GTP-bound RHOQ directs GOPC:CFTR complex to the plasma membrane, thereby rescuing CFTR (Neudauer et al. 2001, Cheng et al. 2005).

RAC1 and CDC42 activate WASP and WAVE proteins, members of the Wiskott-Aldrich Syndrome protein family. WASPs and WAVEs simultaneously interact with G-actin and the actin-related ARP2/3 complex, acting as nucleation promoting factors in actin polymerization (reviewed by Lane et al. 2014).

RHOA, RHOB, RHOC, RAC1 and CDC42 activate a subset of formin family members. Once activated, formins bind G-actin and the actin-bound profilins and accelerate actin polymerization, while some formins also interact with microtubules. Formin-mediated cytoskeletal reorganization plays important roles in cell motility, organelle trafficking and mitosis (reviewed by Kuhn and Geyer 2014).

Rhotekin (RTKN) and rhophilins (RHPN1 and RHPN2) are effectors of RHOA, RHOB and RHOC and have not been studied in detail. They regulate the organization of the actin cytoskeleton and are implicated in the establishment of cell polarity, cell motility and possibly endosome trafficking (Sudo et al. 2006, Watanabe et al. 1996, Fujita et al. 2000, Peck et al. 2002, Mircescu et al. 2002). Similar to formins (Miralles et al. 2003), cytoskeletal changes triggered by RTKN activation may lead to stimulation of SRF-mediated transcription (Reynaud et al. 2000).

RHO GTPases RAC1 and RAC2 are needed for activation of NADPH oxidase complexes 1, 2 and 3 (NOX1, NOX2 and NOX3), membrane associated enzymatic complexes that use NADPH as an electron donor to reduce oxygen and produce superoxide (O2-). Superoxide serves as a secondary messenger and also directly contributes to the microbicidal activity of neutrophils (Knaus et al. 1991, Roberts et al. 1999, Kim and Dinauer 2001, Jyoti et al. 2014, Cheng et al. 2006, Miyano et al. 2006, Ueyama et al. 2006).

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