RHO GTPases Activate ROCKs

Stable Identifier
R-HSA-5627117
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Pathway
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Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
8662509 Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase)

Kimura, K, Ito, M, Amano, M, Chihara, K, Fukata, Y, Nakafuku, M, Yamamori, B, Feng, J, Nakano, T, Okawa, K, Iwamatsu, A, Kaibuchi, K

Science 1996
8702756 Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase)

Amano, M, Ito, M, Kimura, K, Fukata, Y, Chihara, K, Nakano, T, Matsuura, Y, Kaibuchi, K

J Biol Chem 1996
8816443 The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton

Leung, T, Chen, XQ, Manser, E, Lim, L

Mol. Cell. Biol. 1996
17151359 Regulation of myosin II dynamics by phosphorylation and dephosphorylation of its light chain in epithelial cells

Watanabe, T, Hosoya, H, Yonemura, S

Mol Biol Cell 2007
8617235 The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase

Ishizaki, T, Maekawa, M, Fujisawa, K, Okawa, K, Iwamatsu, A, Fujita, A, Watanabe, N, Saito, Y, Kakizuka, A, Morii, N, Narumiya, S

EMBO J 1996
11018042 Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase

Sumi, T, Matsumoto, K, Nakamura, T

J Biol Chem 2001
10652353 Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop

Ohashi, K, Nagata, K, Maekawa, M, Ishizaki, T, Narumiya, S, Mizuno, K

J Biol Chem 2000
20803696 Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity

Amano, M, Nakayama, M, Kaibuchi, K

Cytoskeleton (Hoboken) 2010
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