RHO GTPases activate PKNs (Homo sapiens)

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7, 9-11, 14...27, 31, 449, 10, 15, 25, 26, 4323, 30, 365, 32, 34, 4218366, 35, 37, 387, 197, 11, 191nucleoplasmcytosolYWHAQ androst-4-en-3,17-dione MYL12B CDC25CCDC25C AR YWHAE 6-Dehydrotestosterone PI(3,4,5)P3 RHOA,RHOB,RHOC,RAC1:GTP:PKN1-3:PDPK1:PIP3Piandrost-4-en-3,17-dione p-S216-CDC25C Myosin phosphataseMYH10 RHOC YWHAZ PKN1 MYH9 p-T774-PKN1 PPP1R12A ADPp-T774-PKN1 PPP1R12A p-S216-CDC25CTEST MYH14 ADPRHOA RHOB p-T774-PKN1PKN2 GTP Cell CycleCheckpointsYWHAB RHOA,RHOB,RHOC,RAC1:GTPRHO GTPases activateCITYWHAZ TEST PDPK1:PIP3MYH11 MYL9 PIP3 activates AKTsignalingPPP1CB PDPK1 GTP p-T774-PKN1:AR:AndrogenMYH11 p-T38-PPP1R14A p-T774-PKN1,p-T816-PKN2,p-T718-PKN3RAC1 Activated PKN1stimulatestranscription of AR(androgen receptor)regulated genesKLK2 and KLK3YWHAQ PPP1R14AATPYWHAG YWHAB Smoothmuscle/non-musclemyosin II14-3-3 dimerYWHAH PPP1CB AR p-T19,S20-MYL9 MYH9 PKN3 6-Dehydrotestosterone PKN1-3DHTEST PKN1 GTP p-S216-CDC25C:14-3-3protein complexRHOC PKN3 RAC1 MYH14 AR:AndrogenPPP1R12B SFN MYL6 Mitotic G2-G2/Mphasesp-T38-PPP1R14APKN3 p-T774-PKN1:CDC25Cp-T19,S20-MYL12B PI(3,4,5)P3 p-T816-PKN2 YWHAH MYL6 PKN1 H2ORHOC p-T774-PKN1 RAC1 ATPPKN2 YWHAG PPP1R12B RHOA,RHOB,RHOC,RAC1:GTP:PKN1-3PDPK1 SFN MLCP:p-T38-PPP1R14AMYH10 p-T19,S20-MRLC-smooth muscle/non-muscle myosin IIDHTEST RHOA p-T718-PKN3 YWHAE ADPRHOB RHOA ATPPKN2 RHOB 2, 4, 13, 16, 17, 20...12, 22, 291, 3, 8362517


Protein kinases N (PKN), also known as protein kinase C-related kinases (PKR) feature a C-terminal serine/threonine kinase domain and three RHO-binding motifs at the N-terminus. RHO GTPases RHOA, RHOB, RHOC and RAC1 bind PKN1, PKN2 and PKN3 (Maesaki et al. 1999, Zhong 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 co-activator PDPK1 (PDK1) (Flynn et al. 2000, Torbett et al. 2003). PDPK1 phosphorylates PKNs on a highly conserved threonine residue in the kinase activation loop, which is a prerequisite for PKN activation. Phosphorylation of other residues might also be involved in activation (Flynn et al. 2000, Torbett et al. 2003, Dettori et al. 2009). PKNs are activated by fatty acids like arachidonic acid and phospholipids in vitro, but the in vivo significance of this activation remains unclear (Palmer et al. 1995, Yoshinaga et al. 1999).

PKNs play important roles in diverse functions, including regulation of cell cycle, receptor trafficking, vesicle transport and apoptosis. PKN is also involved in the ligand-dependent transcriptional activation by the androgen receptor. More than 20 proteins and several peptides have been shown to be phosphorylated by PKN1 and PKN2, including CPI-17 (Hamaguchi et al. 2000), alpha-actinin (Mukai et al. 1997), adducin (Collazos et al. 2011), CDC25C (Misaki et al. 2001), vimentin (Matsuzawa et al. 1997), TRAF1 (Kato et al. 2008), CLIP170 (Collazos et al. 2011) and EGFR (Collazos et al. 2011). There are no known substrates for PKN3 (Collazos et al. 2011). View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 5625740
Reactome version: 61
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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  1. Isagawa T, Takahashi M, Kato T, Mukai H, Ono Y.; ''Involvement of protein kinase PKN1 in G2/M delay caused by arsenite.''; PubMed Europe PMC
  2. Iwasaki T, Murata-Hori M, Ishitobi S, Hosoya H.; ''Diphosphorylated MRLC is required for organization of stress fibers in interphase cells and the contractile ring in dividing cells.''; PubMed Europe PMC
  3. Bassi ZI, Audusseau M, Riparbelli MG, Callaini G, D'Avino PP.; ''Citron kinase controls a molecular network required for midbody formation in cytokinesis.''; PubMed Europe PMC
  4. Graves PR, Lovly CM, Uy GL, Piwnica-Worms H.; ''Localization of human Cdc25C is regulated both by nuclear export and 14-3-3 protein binding.''; PubMed Europe PMC
  5. Gruneberg U, Neef R, Li X, Chan EH, Chalamalasetty RB, Nigg EA, Barr FA.; ''KIF14 and citron kinase act together to promote efficient cytokinesis.''; PubMed Europe PMC
  6. O'Farrell PH.; ''Triggering the all-or-nothing switch into mitosis.''; PubMed Europe PMC
  7. Kato T, Gotoh Y, Hoffmann A, Ono Y.; ''Negative regulation of constitutive NF-kappaB and JNK signaling by PKN1-mediated phosphorylation of TRAF1.''; PubMed Europe PMC
  8. Mukai H, Toshimori M, Shibata H, Takanaga H, Kitagawa M, Miyahara M, Shimakawa M, Ono Y.; ''Interaction of PKN with alpha-actinin.''; PubMed Europe PMC
  9. Misaki K, Mukai H, Yoshinaga C, Oishi K, Isagawa T, Takahashi M, Ohsumi K, Kishimoto T, Ono Y.; ''PKN delays mitotic timing by inhibition of Cdc25C: possible involvement of PKN in the regulation of cell division.''; PubMed Europe PMC
  10. Metzger E, Yin N, Wissmann M, Kunowska N, Fischer K, Friedrichs N, Patnaik D, Higgins JM, Potier N, Scheidtmann KH, Buettner R, Schüle R.; ''Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation.''; PubMed Europe PMC
  11. Blasina A, de Weyer IV, Laus MC, Luyten WH, Parker AE, McGowan CH.; ''A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase.''; PubMed Europe PMC
  12. Zhang W, Benson DL.; ''Targeting and clustering citron to synapses.''; PubMed Europe PMC
  13. Hamaguchi T, Ito M, Feng J, Seko T, Koyama M, Machida H, Takase K, Amano M, Kaibuchi K, Hartshorne DJ, Nakano T.; ''Phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by protein kinase N.''; PubMed Europe PMC
  14. Bruinsma W, Raaijmakers JA, Medema RH.; ''Switching Polo-like kinase-1 on and off in time and space.''; PubMed Europe PMC
  15. Dalal SN, Schweitzer CM, Gan J, DeCaprio JA.; ''Cytoplasmic localization of human cdc25C during interphase requires an intact 14-3-3 binding site.''; PubMed Europe PMC
  16. Lartey J, Smith M, Pawade J, Strachan B, Mellor H, López Bernal A.; ''Up-regulation of myometrial RHO effector proteins (PKN1 and DIAPH1) and CPI-17 (PPP1R14A) phosphorylation in human pregnancy is associated with increased GTP-RHOA in spontaneous preterm labor.''; PubMed Europe PMC
  17. Matsuzawa K, Kosako H, Inagaki N, Shibata H, Mukai H, Ono Y, Amano M, Kaibuchi K, Matsuura Y, Azuma I, Inagaki M.; ''Domain-specific phosphorylation of vimentin and glial fibrillary acidic protein by PKN.''; PubMed Europe PMC
  18. Metzger E, Müller JM, Ferrari S, Buettner R, Schüle R.; ''A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer.''; PubMed Europe PMC
  19. Wang G, Jiang Q, Zhang C.; ''The role of mitotic kinases in coupling the centrosome cycle with the assembly of the mitotic spindle.''; PubMed Europe PMC
  20. Di Cunto F, Calautti E, Hsiao J, Ong L, Topley G, Turco E, Dotto GP.; ''Citron rho-interacting kinase, a novel tissue-specific ser/thr kinase encompassing the Rho-Rac-binding protein Citron.''; PubMed Europe PMC
  21. Zemlickova E, Johannes FJ, Aitken A, Dubois T.; ''Association of CPI-17 with protein kinase C and casein kinase I.''; PubMed Europe PMC
  22. Eto M, Kitazawa T, Brautigan DL.; ''Phosphoprotein inhibitor CPI-17 specificity depends on allosteric regulation of protein phosphatase-1 by regulatory subunits.''; PubMed Europe PMC
  23. Hutchinson CL, Lowe PN, McLaughlin SH, Mott HR, Owen D.; ''Differential binding of RhoA, RhoB, and RhoC to protein kinase C-related kinase (PRK) isoforms PRK1, PRK2, and PRK3: PRKs have the highest affinity for RhoB.''; PubMed Europe PMC
  24. Serres MP, Kossatz U, Chi Y, Roberts JM, Malek NP, Besson A.; ''p27(Kip1) controls cytokinesis via the regulation of citron kinase activation.''; PubMed Europe PMC
  25. Yamashiro S, Totsukawa G, Yamakita Y, Sasaki Y, Madaule P, Ishizaki T, Narumiya S, Matsumura F.; ''Citron kinase, a Rho-dependent kinase, induces di-phosphorylation of regulatory light chain of myosin II.''; PubMed Europe PMC
  26. 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
  27. Zong H, Raman N, Mickelson-Young LA, Atkinson SJ, Quilliam LA.; ''Loop 6 of RhoA confers specificity for effector binding, stress fiber formation, and cellular transformation.''; PubMed Europe PMC
  28. Nakai K, Suzuki Y, Kihira H, Wada H, Fujioka M, Ito M, Nakano T, Kaibuchi K, Shiku H, Nishikawa M.; ''Regulation of myosin phosphatase through phosphorylation of the myosin-binding subunit in platelet activation.''; PubMed Europe PMC
  29. Collazos A, Michael N, Whelan RD, Kelly G, Mellor H, Pang LC, Totty N, Parker PJ.; ''Site recognition and substrate screens for PKN family proteins.''; PubMed Europe PMC
  30. Modha R, Campbell LJ, Nietlispach D, Buhecha HR, Owen D, Mott HR.; ''The Rac1 polybasic region is required for interaction with its effector PRK1.''; PubMed Europe PMC
  31. Dettori R, Sonzogni S, Meyer L, Lopez-Garcia LA, Morrice NA, Zeuzem S, Engel M, Piiper A, Neimanis S, Frödin M, Biondi RM.; ''Regulation of the interaction between protein kinase C-related protein kinase 2 (PRK2) and its upstream kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1).''; PubMed Europe PMC
  32. Madaule P, Furuyashiki T, Reid T, Ishizaki T, Watanabe G, Morii N, Narumiya S.; ''A novel partner for the GTP-bound forms of rho and rac.''; PubMed Europe PMC
  33. Torbett NE, Casamassima A, Parker PJ.; ''Hyperosmotic-induced protein kinase N 1 activation in a vesicular compartment is dependent upon Rac1 and 3-phosphoinositide-dependent kinase 1.''; PubMed Europe PMC
  34. Maesaki R, Ihara K, Shimizu T, Kuroda S, Kaibuchi K, Hakoshima T.; ''The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1.''; PubMed Europe PMC
  35. Metzger E, Wissmann M, Yin N, Müller JM, Schneider R, Peters AH, Günther T, Buettner R, Schüle R.; ''LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription.''; PubMed Europe PMC
  36. Watanabe S, De Zan T, Ishizaki T, Narumiya S.; ''Citron kinase mediates transition from constriction to abscission through its coiled-coil domain.''; PubMed Europe PMC
  37. Katoh K, Kano Y, Amano M, Onishi H, Kaibuchi K, Fujiwara K.; ''Rho-kinase--mediated contraction of isolated stress fibers.''; PubMed Europe PMC
  38. Yoshinaga C, Mukai H, Toshimori M, Miyamoto M, Ono Y.; ''Mutational analysis of the regulatory mechanism of PKN: the regulatory region of PKN contains an arachidonic acid-sensitive autoinhibitory domain.''; PubMed Europe PMC
  39. Camera P, da Silva JS, Griffiths G, Giuffrida MG, Ferrara L, Schubert V, Imarisio S, Silengo L, Dotti CG, Di Cunto F.; ''Citron-N is a neuronal Rho-associated protein involved in Golgi organization through actin cytoskeleton regulation.''; PubMed Europe PMC
  40. Owen D, Lowe PN, Nietlispach D, Brosnan CE, Chirgadze DY, Parker PJ, Blundell TL, Mott HR.; ''Molecular dissection of the interaction between the small G proteins Rac1 and RhoA and protein kinase C-related kinase 1 (PRK1).''; PubMed Europe PMC
  41. Hutchinson CL, Lowe PN, McLaughlin SH, Mott HR, Owen D.; ''Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1.''; PubMed Europe PMC
  42. Peng CY, Graves PR, Thoma RS, Wu Z, Shaw AS, Piwnica-Worms H.; ''Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.''; PubMed Europe PMC
  43. Palmer RH, Dekker LV, Woscholski R, Le Good JA, Gigg R, Parker PJ.; ''Activation of PRK1 by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. A comparison with protein kinase C isotypes.''; PubMed Europe PMC
  44. Flynn P, Mellor H, Casamassima A, Parker PJ.; ''Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase.''; PubMed Europe PMC


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93349view11:21, 9 August 2017ReactomeTeamreactome version 61
89087view08:03, 22 August 2016EgonwOntology Term : 'signaling pathway' added !
86433view09:18, 11 July 2016ReactomeTeamreactome version 56
83151view10:10, 18 November 2015ReactomeTeamVersion54
81504view13:02, 21 August 2015ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
14-3-3 dimerComplexR-HSA-1445138 (Reactome)
6-Dehydrotestosterone MetaboliteCHEBI:29117 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
AR ProteinP10275 (Uniprot-TrEMBL)
AR:AndrogenComplexR-HSA-5625732 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated PKN1

stimulates transcription of AR (androgen receptor) regulated genes

KLK2 and KLK3
PathwayR-HSA-5625886 (Reactome) PKN1, activated by phosphorylation at threonine T774, binds activated AR (androgen receptor) and promotes transcription from AR-regulated promoters. On one hand, phosphorylated PKN1 promotes the formation of a functional complex of AR with the transcriptional coactivator NCOA2 (TIF2) (Metzger et al. 2003). On the other hand, binding of phosphorylated PKN1, in complex with the activated AR, to androgen-reponsive promoters of KLK2 and KLK3 (PSA) genes, leads to PKN1-mediated histone phosphorylation. PKN1-phosphorylated histones recruit histone demethylases KDM4C (JMJD2C) and KDM1A (LSD1), and the ensuing demethylation of histones associated with the promoter regions of KLK2 and KLK3 genes increases their transcription (Metzger et al. 2005, Metzger et al. 2008).
CDC25C ProteinP30307 (Uniprot-TrEMBL)
CDC25CProteinP30307 (Uniprot-TrEMBL)
Cell Cycle CheckpointsPathwayR-HSA-69620 (Reactome) A hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell cycle progression ensuring an interdependency of S-phase and mitosis, the integrity of the genome and the fidelity of chromosome segregation.

Checkpoints are layers of control that act to delay CDK activation when defects in the division program occur. As the CDKs functioning at different points in the cell cycle are regulated by different means, the various checkpoints differ in the biochemical mechanisms by which they elicit their effect. However, all checkpoints share a common hierarchy of a sensor, signal transducers, and effectors that interact with the CDKs.

The stability of the genome in somatic cells contrasts to the almost universal genomic instability of tumor cells. There are a number of documented genetic lesions in checkpoint genes, or in cell cycle genes themselves, which result either directly in cancer or in a predisposition to certain cancer types. Indeed, restraint over cell cycle progression and failure to monitor genome integrity are likely prerequisites for the molecular evolution required for the development of a tumor. Perhaps most notable amongst these is the p53 tumor suppressor gene, which is mutated in >50% of human tumors. Thus, the importance of the checkpoint pathways to human biology is clear.

DHTEST MetaboliteCHEBI:16330 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
MLCP:p-T38-PPP1R14AComplexR-HSA-5671771 (Reactome)
MYH10 ProteinP35580 (Uniprot-TrEMBL)
MYH11 ProteinP35749 (Uniprot-TrEMBL)
MYH14 ProteinQ7Z406 (Uniprot-TrEMBL)
MYH9 ProteinP35579 (Uniprot-TrEMBL)
MYL12B ProteinO14950 (Uniprot-TrEMBL)
MYL6 ProteinP60660 (Uniprot-TrEMBL)
MYL9 ProteinP24844 (Uniprot-TrEMBL)
Mitotic G2-G2/M phasesPathwayR-HSA-453274 (Reactome) Mitotic G2 (gap 2) phase is the second growth phase during eukaryotic mitotic cell cycle. G2 encompasses the interval between the completion of DNA synthesis and the beginning of mitosis. During G2, the cytoplasmic content of the cell increases. At G2/M transition, duplicated centrosomes mature and separate and CDK1:cyclin B complexes become active, setting the stage for spindle assembly and chromosome condensation that occur in the prophase of mitosis (O'Farrell 2001, Bruinsma et al. 2012, Jiang et al. 2014).
Myosin phosphataseComplexR-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.
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1:PIP3ComplexR-HSA-377179 (Reactome)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PKN1 ProteinQ16512 (Uniprot-TrEMBL)
PKN1-3ComplexR-HSA-5623626 (Reactome)
PKN2 ProteinQ16513 (Uniprot-TrEMBL)
PKN3 ProteinQ6P5Z2 (Uniprot-TrEMBL)
PPP1CB ProteinP62140 (Uniprot-TrEMBL)
PPP1R12A ProteinO14974 (Uniprot-TrEMBL)
PPP1R12B ProteinO60237 (Uniprot-TrEMBL)
PPP1R14AProteinQ96A00 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RHO GTPases activate CITPathwayR-HSA-5625900 (Reactome) Citron kinase (CIT) or citron RHO-interacting kinase (CRIK) shares similarities with ROCK kinases. Like ROCK, it consists of a serine/threonine kinase domain, a coiled-coil region, a RHO-binding domain, a cysteine rich region and a plekstrin homology (PH) domain, but additionally features a proline-rich region and a PDZ-binding domain. A shorter splicing isoform of CIT, citron-N, is specifically expressed in the nervous system and lacks the kinase domain. Citron-N is a component of the post-synaptic density, where it binds to the PDZ domains of the scaffolding protein PDS-95/SAP90 (Zhang et al. 2006).

While the binding of CIT to RHO GTPases RHOA, RHOB, RHOC and RAC1 is well established (Madaule et al. 1995), the mechanism of CIT activation by GTP-bound RHO GTPases has not been elucidated. There are indications that CIT may be activated through autophosphorylation in the presence of active forms of RHO GTPases (Di Cunto et al. 1998). CIT appears to phosphorylate the myosin regulatory light chain (MRLC), the only substrate identified to date, on the same residues that are phosphorylated by ROCKs, but it has not been established yet how this relates to activation by RHO GTPases (Yamashiro et al. 2003). 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) and p27(Kip1) (Serres et al. 2012).

RHOA ProteinP61586 (Uniprot-TrEMBL)
RHOA,RHOB,RHOC,RAC1:GTP:PKN1-3:PDPK1:PIP3ComplexR-HSA-5623637 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:PKN1-3ComplexR-HSA-5623624 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTPComplexR-HSA-5624294 (Reactome)
RHOB ProteinP62745 (Uniprot-TrEMBL)
RHOC ProteinP08134 (Uniprot-TrEMBL)
SFN ProteinP31947 (Uniprot-TrEMBL)


myosin II
ComplexR-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.
TEST MetaboliteCHEBI:17347 (ChEBI)
YWHAB ProteinP31946 (Uniprot-TrEMBL)
YWHAE ProteinP62258 (Uniprot-TrEMBL)
YWHAG ProteinP61981 (Uniprot-TrEMBL)
YWHAH ProteinQ04917 (Uniprot-TrEMBL)
YWHAQ ProteinP27348 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
androst-4-en-3,17-dione MetaboliteCHEBI:16422 (ChEBI)
p-S216-CDC25C ProteinP30307 (Uniprot-TrEMBL)
p-S216-CDC25C:14-3-3 protein complexComplexR-HSA-75005 (Reactome)
p-S216-CDC25CProteinP30307 (Uniprot-TrEMBL)
p-T19,S20-MRLC-smooth muscle/non-muscle myosin IIComplexR-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 ProteinO14950 (Uniprot-TrEMBL)
p-T19,S20-MYL9 ProteinP24844 (Uniprot-TrEMBL)
p-T38-PPP1R14A ProteinQ96A00 (Uniprot-TrEMBL)
p-T38-PPP1R14AProteinQ96A00 (Uniprot-TrEMBL)
p-T718-PKN3 ProteinQ6P5Z2 (Uniprot-TrEMBL)
p-T774-PKN1 ProteinQ16512 (Uniprot-TrEMBL)
p-T774-PKN1,p-T816-PKN2,p-T718-PKN3ComplexR-HSA-5623659 (Reactome)
p-T774-PKN1:AR:AndrogenComplexR-HSA-5625734 (Reactome)
p-T774-PKN1:CDC25CComplexR-HSA-5671748 (Reactome)
p-T774-PKN1ProteinQ16512 (Uniprot-TrEMBL)
p-T816-PKN2 ProteinQ16513 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
14-3-3 dimerR-HSA-75016 (Reactome)
ADPArrowR-HSA-5623667 (Reactome)
ADPArrowR-HSA-5671749 (Reactome)
ADPArrowR-HSA-5671763 (Reactome)
AR:AndrogenR-HSA-5625717 (Reactome)
ATPR-HSA-5623667 (Reactome)
ATPR-HSA-5671749 (Reactome)
ATPR-HSA-5671763 (Reactome)
CDC25CR-HSA-5671737 (Reactome)
H2OR-HSA-419232 (Reactome)
MLCP:p-T38-PPP1R14AArrowR-HSA-5671772 (Reactome)
Myosin phosphataseR-HSA-5671772 (Reactome)
Myosin phosphatasemim-catalysisR-HSA-419232 (Reactome)
PDPK1:PIP3ArrowR-HSA-5623667 (Reactome)
PDPK1:PIP3R-HSA-5623632 (Reactome)
PKN1-3R-HSA-5623622 (Reactome)
PPP1R14AR-HSA-5671763 (Reactome)
PiArrowR-HSA-419232 (Reactome)
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).
R-HSA-5623622 (Reactome) Each protein kinase C related kinase - PKN1 (PRK1), PKN2 (PRK2) and PKN3 (PRK3) - possesses three RHO binding motifs known as HR1 (REM) domains - HR1a (REM1), HR1b (REM2) and HR1c (REM3) located at the N-termini of PKN1, PKN2 and PKN3. These domains mediate the binding of each kinase to any of the three RHO family GTPases: RHOA, RHOB and RHOC. HR1 domains of PKN1, PKN2 and PKN3 contain anti-parallel coiled-coil finger (ACC finger) folds (Maesaki et al. 1999, Hutchinson et al. 2011, Hutchinson et al. 2013). RHO GTPase RAC1 also binds and activates PKN1 (Owen et al. 2003, Modha et al. 2008), with the interaction involving HR1a and HR1b RHO-binding motifs of PKN1 and the polybasic region of RAC1, and it also binds to PKN2 (Zong et al. 1999). Binding of RAC1 to PKN3 is likely, based on sequence similarity, but has not been experimentally investigated.
R-HSA-5623632 (Reactome) Binding of PKN1, PKN2 or PKN3 to any of the RHO GTP-ases RHOA, RHOB, RHOC or RAC1 enables PKN1, PKN2 and PKN3 to interact with PIP3-activated kinase PDPK1, through the formation of ternary complexes (Flynn et al. 2000, Torbett et al. 2003).
R-HSA-5623667 (Reactome) PDPK1 (PDK1) phosphorylates PKN1, PKN2 and likely PKN3 on a highly conserved threonine residue (T774 of PKN1, T816 of PKN2, T718 of PKN3) in the kinase activation loop. Although phosphorylation of PKN1, PKN2 and PKN3 at other sites may be needed for them to achieve the full catalytic activity, PDPK1-mediated phosphorylation of the activation loop is a necessary step in PKN1, PKN2 and likely PKN3 activation. This reaction happens while the PKN protein is complexed with a RHO GTPase and PIP3-bound PDPK1 (Flynn et al. 2000, Torbett et al. 2003, Dettori et al. 2009).
R-HSA-5625717 (Reactome) Activated PKN1 binds androgen-activated AR (androgen receptor) (Metzger et al. 2003).
R-HSA-5671737 (Reactome) Activated PKN1 (p-T774-PKN1) binds CDC25C (Isigawa et al. 2005).
R-HSA-5671749 (Reactome) Activated PKN1 (p-T774-PKN1) phosphorylates CDC25C on serine residue S216. This leads to increased binding of CDC25C to 14-3-3 proteins, retention of CDC25C in the cytosol, and delayed mitotic entry (Misaki et al. 2001, Isigawa et al. 2005, Collazos et al. 2011).
R-HSA-5671763 (Reactome) Activated PKN1 (p-T774-PKN1) phosphorylates PPP1R14A (CPI-17), an inhibitor of myosin light chain phosphatase complex (MLPC), on threonine residue T38 (Hamaguchi et al. 2000), and high levels of PKN1 activity correlate with high levels of PPP1R14A phosphorylation (Lartey et al. 2007). It is not certain that PKN1 can directly bind PPP1R14A, and C family protein kinases (PKCs) may be the main PPP1R14A kinases (Zemlickova et al. 2004).
R-HSA-5671772 (Reactome) PPP1R14A (CPI-17) phosphorylated on threonine T38 binds MLCP (myosin light chain phosphatase complex) and inhibits its catalytic activity. PPP1R14A simultanously associates with the MLCP catalytic subunit (PP1CB) and the regulatory subunit MYPT1 (PPP1R12A) (Eto et al. 2004).
R-HSA-75016 (Reactome) CDC25C is phosphorylated by CHK1 at ser-216 (Blasina et al.,1999 ) resulting in both inhibition of the CDC25 phosphatase activity and creation of a 14-3-3 docking site (Peng et al., 1997). Association of 14-3-3 proteins with phosphorylated CDC25C (p-S216-CDC25C) is thought to result in retention of this complex within the cytoplasm (Dalal et al., 1999; Graves et al, 2001).
RHOA,RHOB,RHOC,RAC1:GTP:PKN1-3:PDPK1:PIP3ArrowR-HSA-5623632 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:PKN1-3:PDPK1:PIP3mim-catalysisR-HSA-5623667 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:PKN1-3ArrowR-HSA-5623622 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTP:PKN1-3R-HSA-5623632 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTPArrowR-HSA-5623667 (Reactome)
RHOA,RHOB,RHOC,RAC1:GTPR-HSA-5623622 (Reactome)


myosin II
ArrowR-HSA-419232 (Reactome)
p-S216-CDC25C:14-3-3 protein complexArrowR-HSA-75016 (Reactome)
p-S216-CDC25CArrowR-HSA-5671749 (Reactome)
p-S216-CDC25CR-HSA-75016 (Reactome)
p-T19,S20-MRLC-smooth muscle/non-muscle myosin IIR-HSA-419232 (Reactome)
p-T38-PPP1R14AArrowR-HSA-5671763 (Reactome)
p-T38-PPP1R14AR-HSA-5671772 (Reactome)
p-T774-PKN1,p-T816-PKN2,p-T718-PKN3ArrowR-HSA-5623667 (Reactome)
p-T774-PKN1:AR:AndrogenArrowR-HSA-5625717 (Reactome)
p-T774-PKN1:CDC25CArrowR-HSA-5671737 (Reactome)
p-T774-PKN1:CDC25CR-HSA-5671749 (Reactome)
p-T774-PKN1:CDC25Cmim-catalysisR-HSA-5671749 (Reactome)
p-T774-PKN1ArrowR-HSA-5671749 (Reactome)
p-T774-PKN1R-HSA-5625717 (Reactome)
p-T774-PKN1R-HSA-5671737 (Reactome)
p-T774-PKN1mim-catalysisR-HSA-5671763 (Reactome)

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