RHO GTPases activate ROCKs (Homo sapiens)

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1. Watanabe T, Hosoya H, Yonemura S.; ''Regulation of myosin II dynamics by phosphorylation and dephosphorylation of its light chain in epithelial cells.''; PubMed Europe PMC Scholia
2. Sebbagh M, Hamelin J, Bertoglio J, Solary E, Bréard J.; ''Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner.''; PubMed Europe PMC Scholia
3. Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S.; ''The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase.''; PubMed Europe PMC Scholia
4. Pasterkamp RJ, Verhaagen J.; ''Semaphorins in axon regeneration: developmental guidance molecules gone wrong?''; PubMed Europe PMC Scholia
5. Leung T, Chen XQ, Manser E, Lim L.; ''The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton.''; PubMed Europe PMC Scholia
6. Araki S, Ito M, Kureishi Y, Feng J, Machida H, Isaka N, Amano M, Kaibuchi K, Hartshorne DJ, Nakano T.; ''Arachidonic acid-induced Ca2+ sensitization of smooth muscle contraction through activation of Rho-kinase.''; PubMed Europe PMC Scholia
7. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K.; ''Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase)''; PubMed Europe PMC Scholia
8. Zhang B, Chernoff J, Zheng Y.; ''Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA.''; PubMed Europe PMC Scholia
9. Dickson BJ.; ''Molecular mechanisms of axon guidance.''; PubMed Europe PMC Scholia
10. Jung JH, Traugh JA.; ''Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141.''; PubMed Europe PMC Scholia
11. Ikebe M, Hartshorne DJ.; ''Phosphorylation of smooth muscle myosin at two distinct sites by myosin light chain kinase.''; PubMed Europe PMC Scholia
12. Ohashi K, Nagata K, Maekawa M, Ishizaki T, Narumiya S, Mizuno K.; ''Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop.''; PubMed Europe PMC Scholia
13. Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L.; ''A brain serine/threonine protein kinase activated by Cdc42 and Rac1.''; PubMed Europe PMC Scholia
14. Wang J, Wu JW, Wang ZX.; ''Mechanistic studies of the autoactivation of PAK2: a two-step model of cis initiation followed by trans amplification.''; PubMed Europe PMC Scholia
15. Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF.; ''Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I.''; PubMed Europe PMC Scholia
16. Pasterkamp RJ, Kolodkin AL.; ''Semaphorin junction: making tracks toward neural connectivity.''; PubMed Europe PMC Scholia
17. Lei M, Lu W, Meng W, Parrini MC, Eck MJ, Mayer BJ, Harrison SC.; ''Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch.''; PubMed Europe PMC Scholia
18. Zhou Y, Gunput RA, Pasterkamp RJ.; ''Semaphorin signaling: progress made and promises ahead.''; PubMed Europe PMC Scholia
19. Ikebe M, Koretz J, Hartshorne DJ.; ''Effects of phosphorylation of light chain residues threonine 18 and serine 19 on the properties and conformation of smooth muscle myosin.''; PubMed Europe PMC Scholia
20. Szczepanowska J.; ''Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements.''; PubMed Europe PMC Scholia
21. Koncina E, Roth L, Gonthier B, Bagnard D.; ''Role of semaphorins during axon growth and guidance.''; PubMed Europe PMC Scholia
22. Chan PM, Manser E.; ''PAKs in human disease.''; PubMed Europe PMC Scholia
23. Amano M, Nakayama M, Kaibuchi K.; ''Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity.''; PubMed Europe PMC Scholia
24. Daniels RH, Bokoch GM.; ''p21-activated protein kinase: a crucial component of morphological signaling?''; PubMed Europe PMC Scholia
25. Ueda K, Murata-Hori M, Tatsuka M, Hosoya H.; ''Rho-kinase contributes to diphosphorylation of myosin II regulatory light chain in nonmuscle cells.''; PubMed Europe PMC Scholia
26. Chong C, Tan L, Lim L, Manser E.; ''The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity.''; PubMed Europe PMC Scholia
27. Pandey D, Pandey D, Goyal P, Bamburg JR, Siess W.; ''Regulation of LIM-kinase 1 and cofilin in thrombin-stimulated platelets.''; PubMed Europe PMC Scholia
28. Sumi T, Matsumoto K, Nakamura T.; ''Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase.''; PubMed Europe PMC Scholia
29. Manser E, Chong C, Zhao ZS, Leung T, Michael G, Hall C, Lim L.; ''Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family.''; PubMed Europe PMC Scholia
30. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K.; ''Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase).''; PubMed Europe PMC Scholia
31. Parrini MC, Lei M, Harrison SC, Mayer BJ.; ''Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1.''; PubMed Europe PMC Scholia

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External references

DataNodes

Name	Type	Database reference	Comment
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activated ROCK:RhoA/B/C:GTP	Complex	R-HSA-422483 (Reactome)
GTP	Metabolite	CHEBI:15996 (ChEBI)
H2O	Metabolite	CHEBI:15377 (ChEBI)
LIM Kinases	Complex	R-HSA-419708 (Reactome)
LIMK1	Protein	P53667 (Uniprot-TrEMBL)
LIMK2	Protein	P53671 (Uniprot-TrEMBL)
MYH10	Protein	P35580 (Uniprot-TrEMBL)
MYH11	Protein	P35749 (Uniprot-TrEMBL)
MYH14	Protein	Q7Z406 (Uniprot-TrEMBL)
MYH9	Protein	P35579 (Uniprot-TrEMBL)
MYL12B	Protein	O14950 (Uniprot-TrEMBL)
MYL6	Protein	P60660 (Uniprot-TrEMBL)
MYL9	Protein	P24844 (Uniprot-TrEMBL)
Myosin phosphatase	Complex	R-HSA-419080 (Reactome)	All known myosin phosphatases consist of PP1 beta and both a large and a small myosin phosphatase targetting (Mypt) subunit. The large Mypt targets PP1 beta to myosin and determines the substrate specifity of the phosphatase. The Large Mypt subunit is encoded by one of three human genes, PPP1R12A (MYPT1), PPP1R12B (MYPT2) and PPP1R12C. Only MYPT1 is represented here. The small subunit is an alternative transcript of MYPT2. The function of the small Mypt subunit remains unclear, but because it is known to interact directly with myosin and the large Mypt it is thought to have an unspecified regulatory role.
PPP1CB	Protein	P62140 (Uniprot-TrEMBL)
PPP1R12A	Protein	O14974 (Uniprot-TrEMBL)
PPP1R12B	Protein	O60237 (Uniprot-TrEMBL)
Pi	Metabolite	CHEBI:18367 (ChEBI)
RHO GTPases activate PAKs	Pathway	R-HSA-5627123 (Reactome)	The PAKs (p21-activated kinases) are a family of serine/threonine kinases mainly implicated in cytoskeletal rearrangements. All PAKs share a conserved catalytic domain located at the carboxyl terminus and a highly conserved motif in the amino terminus known as p21-binding domain (PBD) or Cdc42/Rac interactive binding (CRIB) domain. There are six mammalian PAKs that can be divided into two classes: class I (or conventional) PAKs (PAK1-3) and class II PAKs (PAK4-6). Conventional PAKs are important regulators of cytoskeletal dynamics and cell motility and are additionally implicated in transcription through MAPK (mitogen-activated protein kinase) cascades, death and survival signaling and cell cycle progression (Chan and Manser 2012). PAK1, PAK2 and PAK3 are direct effectors of RAC1 and CDC42 GTPases. RAC1 and CDC42 bind to the CRIB domain. This binding induces a conformational change that disrupts inactive PAK homodimers and relieves autoinhibition of the catalytic carboxyl terminal domain (Manser et al. 1994, Manser et al. 1995, Zhang et al. 1998, Lei et al. 2000, Parrini et al. 2002; reviewed by Daniels and Bokoch 1999, Szczepanowska 2009). Autophosphorylation of a conserved threonine residue in the catalytic domain of PAKs (T423 in PAK1, T402 in PAK2 and T436 in PAK3) is necessary for the kinase activity of PAK1, PAK2 and PAK3. Autophosphorylation of PAK1 serine residue S144, PAK2 serine residue S141, and PAK3 serine residue S154 disrupts association of PAKs with RAC1 or CDC42 and enhances kinase activity (Lei et al. 2000, Chong et al. 2001, Parrini et al. 2002, Jung and Traugh 2005, Wang et al. 2011). LIMK1 is one of the downstream targets of PAK1 and is activated through PAK1-mediated phosphorylation of the threonine residue T508 within its activation loop (Edwards et al. 1999). Further targets are the myosin regulatory light chain (MRLC), myosin light chain kinase (MLCK), filamin, cortactin, p41Arc (a subunit of the Arp2/3 complex), caldesmon, paxillin and RhoGDI, to mention a few (Szczepanowska 2009). Class II PAKs also have a CRIB domain, but lack a defined autoinhibitory domain and proline-rich regions. They do not require GTPases for their kinase activity, but their interaction with RAC or CDC42 affects their subcellular localization. Only conventional PAKs will be annotated here.
RHOA	Protein	P61586 (Uniprot-TrEMBL)
RHOA/B/C:GTP	Complex	R-HSA-419161 (Reactome)
RHOB	Protein	P62745 (Uniprot-TrEMBL)
RHOC	Protein	P08134 (Uniprot-TrEMBL)
ROCK1	Protein	Q13464 (Uniprot-TrEMBL)
ROCK1,ROCK2	Complex	R-HSA-419057 (Reactome)	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.
ROCK2	Protein	O75116 (Uniprot-TrEMBL)
Semaphorin interactions	Pathway	R-HSA-373755 (Reactome)	Semaphorins are a large family of cell surface and secreted guidance molecules divided into eight classes on the basis of their structures. They all have an N-terminal conserved sema domain. Semaphorins signal through multimeric receptor complexes that include other proteins such as plexins and neuropilins.
Smooth muscle/non-muscle myosin II	Complex	R-HSA-419194 (Reactome)	Class 2 myosins are a set of protein complexes that bind actin and hydrolyse ATP, acting as molecular motors. They consist of two myosin heavy chains , two essential light chains and two regulatory light chains (MRLCs). Smooth muscle and non-muscle myosin isoforms are a subset of Class 2 myosin complexes. The nomenclature for isoforms is misleading, as non-muscle isoforms can be found in smooth muscle. The 4 smooth muscle isoforms all have heavy chains encoded by MYH11. The non-muscle isoforms have heavy chains encoded by MYH9, MYH10 or MYH14 (NMHC-IIA, B and C). The essential light chain (LC17) common to smooth and non-muscle isoforms is encoded by MYL6. The regulatory light chain (LC20) is encoded by either MYL9, giving a slightly more basic protein that is referred to as the smooth muscle LC20 isoform, and MRLC2, giving a more acidic isoform referred to as the non-muscle LC20 isoform. Class 2 myosins play a crucial role in a variety of cellular processes, including cell migration, polarity formation, and cytokinesis.
p-LIMK	Complex	R-HSA-419709 (Reactome)
p-T19,S20-MRLC-smooth muscle/non-muscle myosin II	Complex	R-HSA-419195 (Reactome)	Nonmuscle myosin II (NMM2) is an actin-based motor protein that plays a crucial role in a variety of cellular processes, including smooth muscle contraction, cell migration, polarity formation, and cytokinesis. NMM2 consists of two myosin heavy chains encoded by MYH9, MYH10, MYH14 (NMHC-IIA, B and C) or MYH11, two copies of MYL6 essential light chain protein, and two regulatory light chains (MRLCs), MYL9 and MYL12B. Myosin II activity is stimulated by phosphorylation of MRLC. Diphosphorylation at Thr-19 and Ser-20 (commonly referred in the literature as Thr-18 and Ser-19) increases both actin-activated Mg2+ ATPase activity and the stability of myosin II filaments; monophosphorylation at Ser-20 is less effective (Ikebe and Hartshorne 1985, Ikebe et al. 1988). Kinases responsible for the phosphorylation include myosin light chain kinase (MLCK), ROCK kinase, citron kinase, myotonic dystrophy kinase-related CDC42-binding protein kinase, and Zipper-interacting protein (ZIP) kinase. ROCK activity has been shown to regulate MRLC phosphorylation by directly mono- or diphosphorylating MRLC (Amano et al., 1996, Ueda et al., 2002, Watanabe et al. 2007).
p-T19,S20-MYL12B	Protein	O14950 (Uniprot-TrEMBL)
p-T19,S20-MYL9	Protein	P24844 (Uniprot-TrEMBL)
p-T505-LIMK2	Protein	P53671 (Uniprot-TrEMBL)
p-T508-LIMK1	Protein	P53667 (Uniprot-TrEMBL)
p-T696,S852-MYPT1-Myosin Phosphatase	Complex	R-HSA-419085 (Reactome)	All known myosin phosphatases consist of PP1 beta and both a large and a small myosin phosphatase targetting (Mypt) subunit. The large Mypt targets PP1 beta to myosin and determines the substrate specifity of the phosphatase. The Large Mypt subunit is encoded by one of three human genes, PPP1R12A (MYPT1), PPP1R12B (MYPT2) and PPP1R12C. Only MYPT1 is represented here. The small subunit is an alternative transcript of MYPT2. The function of the small Mypt subunit remains unclear, but because it is known to interact directly with myosin and the large Mypt it is thought to have an unspecified regulatory role.
p-T696,S852-PPP1R12A	Protein	O14974 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ADP	Arrow	R-HSA-419083 (Reactome)
	ADP	Arrow	R-HSA-419087 (Reactome)
	ADP	Arrow	R-HSA-419197 (Reactome)
ATP			R-HSA-419083 (Reactome)
ATP			R-HSA-419087 (Reactome)
ATP			R-HSA-419197 (Reactome)
	Activated ROCK:RhoA/B/C:GTP	Arrow	R-HSA-419049 (Reactome)
Activated ROCK:RhoA/B/C:GTP		mim-catalysis	R-HSA-419083 (Reactome)
Activated ROCK:RhoA/B/C:GTP		mim-catalysis	R-HSA-419087 (Reactome)
Activated ROCK:RhoA/B/C:GTP		mim-catalysis	R-HSA-419197 (Reactome)
H2O			R-HSA-419232 (Reactome)
LIM Kinases			R-HSA-419087 (Reactome)
Myosin phosphatase			R-HSA-419083 (Reactome)
Myosin phosphatase		mim-catalysis	R-HSA-419232 (Reactome)
	Pi	Arrow	R-HSA-419232 (Reactome)
			R-HSA-419049 (Reactome)	ROCKs are primarily known as downstream effectors of RHO, but they can also be activated by arachidonic acid, which binds to the pleckstrin homology domain, releasing an autoinhibitory loop within ROCK and allowing catalytic activity (Araki et al. 2001). Proteolytic cleavage at the C-terminus by caspase-3 and granzyme B also activates ROCK1 and ROCK2, causing plasma membrane blebbing during apoptosis (Coleman et al. 2001, Sebbagh et al. 2005). Multiple targets of ROCK contribute to the stabilization of actin filaments and the generation of actin-myosin contractile force.
			R-HSA-419083 (Reactome)	The activity of nonmuscle myosin II (NMM2) is suppressed by dephosphorylation of myosin regulatory light chains (MRLC), MYL9 and MYL12B, by the MLC phosphatase. The MLC phosphatase is composed of a catalytic subunit (PPP1CB) and two regulatory subunits, myosin phosphatase-targeting subunit 1 (MYPT1, PPP1R12A) and M20 (MYPT2, PPP1R12B). MYPT1 binds directly to myosin II. Myosin phosphatase is inhibited by ROCKs. ROCKs phosphorylate MYPT1 subunit of the myosin phosphatase at two inhibitory sites, Thr696 and Ser852, resulting in a decrease in MRLC phosphatase activity and an increase in phosphorylated MRLC (Kimura et al. 1996, Nakai et al. 1997, Katoh et al. 2001, Iwasaki et al. 2001), which promotes binding to filamentous actin and stress fibre formation. This effect is synergistic with the direct phosphorylation of MRLC by ROCKs.
			R-HSA-419087 (Reactome)	LIM kinases are serine protein kinases with a unique combination of two N-terminal LIM motifs, a central PDZ domain, and a C-terminal protein kinase domain. ROCK1 and ROCK2 phosphorylate and activate LIM kinases LIMK1 and LIMK2 at Thr508 and Thr505, respectively (Ohashi et al. 2000, Sumi et al. 2001). These threonine residues lay within the activation loop of the kinase domain. LIMKs phosphorylate and inactivate cofilin, an actin depolymerizing factor, resulting in stabilization of the actin cytoskeleton (Pandey et al. 2006).
			R-HSA-419197 (Reactome)	Nonmuscle myosin II (NMM2) is an actin-based motor protein that plays a crucial role in a variety of cellular processes, including smooth muscle contraction, cell migration, polarity formation, and cytokinesis. NMM2 consists of two myosin heavy chains encoded by MYH9, MYH10, MYH14 (NMHC-IIA, B and C) or MYH11, two copies of MYL6 essential light chain protein, and two regulatory light chains (MRLCs), MYL9 and MYL12B. Myosin II activity is stimulated by phosphorylation of MRLC. Diphosphorylation at Thr-19 and Ser-20 (commonly referred in the literature as Thr-18 and Ser-19) increases both actin-activated Mg2+ ATPase activity and the stability of myosin II filaments; monophosphorylation at Ser-20 is less effective (Ikebe and Hartshorne 1985, Ikebe et al. 1988). Kinases responsible for the phosphorylation include myosin light chain kinase (MLCK), ROCK kinase, citron kinase, myotonic dystrophy kinase-related CDC42-binding protein kinase, and Zipper-interacting protein (ZIP) kinase. ROCK activity has been shown to regulate MRLC phosphorylation by directly mono- or diphosphorylating MRLC (Amano et al., 1996, Ueda et al., 2002, Watanabe et al. 2007).
			R-HSA-419232 (Reactome)	In non-muscle cells, phosphorylation of myosin II regulates actomyosin contractility. The level of myosin phosphorylation depends mainly on the balance of two enzymes, the Ca2+-dependent MLC kinase (MLCK), and myosin phosphatase (MLCP). Phosphorylation of the regulatory light chain of myosin II (MRLC) induces its interaction with actin, activating myosin ATPase and resulting in enhanced cell contractility. Myosin phosphatase decreases MRLC phosphorylation, which inhibits binding to filamentous actin and stress fibre formation (Kimura et al. 1996, Nakai et al. 1997, Katoh et al. 2001, Iwasaki et al. 2001).
RHOA/B/C:GTP			R-HSA-419049 (Reactome)
ROCK1,ROCK2			R-HSA-419049 (Reactome)
	Smooth muscle/non-muscle myosin II	Arrow	R-HSA-419232 (Reactome)
Smooth muscle/non-muscle myosin II			R-HSA-419197 (Reactome)
	p-LIMK	Arrow	R-HSA-419087 (Reactome)
	p-T19,S20-MRLC-smooth muscle/non-muscle myosin II	Arrow	R-HSA-419197 (Reactome)
p-T19,S20-MRLC-smooth muscle/non-muscle myosin II			R-HSA-419232 (Reactome)
	p-T696,S852-MYPT1-Myosin Phosphatase	Arrow	R-HSA-419083 (Reactome)