Signaling by PTK6 (Homo sapiens)

From WikiPathways

Revision as of 16:22, 26 November 2018 by Marvin M2 (Talk | contribs)
(diff) ←Older revision | Current revision (diff) | Newer revision→ (diff)
Jump to: navigation, search
1, 6, 9, 12, 15...69563, 145, 15622, 10114054, 122, 1319582952340, 117105, 164823527, 10033231141142210027, 10010210512282825451, 67, 11418, 70, 92, 9984, 103, 121709546, 776346, 1451176383, 10411484, 1213561011019510254104114cytosolnucleoplasmHBEGF:EGFR:p-Y525-GPNMBp-Y342-PTK6 UBC(381-456) ADPADPp-Y31,Y118-PXNHRAS Signaling by EGFRPTPN1 ADPRegulation ofHypoxia-inducibleFactor (HIF) byoxygenp-Y342-PTK6:ARHGAP35DOCK1 CDK4 ADPCDKN1B:(CDK4:CCND1,(CDK2:CCNE1))p-Y525-GPNMB ATPATPCCNE1 p-Y435,Y440,Y443-KHDRBS1p-Y342-PTK6:AKT1PTK6 GeneARAP1 p-Y342-PTK6RHOA UBB(1-76) p-Y165,Y664-BCAR1p-Y342-PTK6 p-Y705-STAT3 ARHGAP35 p-Y231-ARAP1HIF1A,EPAS1:PTK6Genep-Y342-PTK6 ADPLRRK2p-Y342-PTK6 KRAS HBEGF(63-148) p-Y342-PTK6 GTP KRAS SOCS3 GeneHBEGF:EGFR:p-Y525-GPNMB:LINC01139:PTK6:LRRK2RHO GTPases activateCITp-Y342-PTK6 Phosphorylated p-Y877-ERBB2 heterodimers PTK6 Gene EPAS1 KHDRBS2p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ELMO2 CBLp-Y1105-ARHGAP35RPS27A(1-76) BCAR1NRAS p-Y525-GPNMB SOCS3LINC01139GDPp-Y362-DOK1RASA1 ATPRHO GTPases activateIQGAPsPTK6 Gene p-Y342-PTK6 H2Op-Y342-PTK6:p-Y250-STAP2p-Y342-PTK6 STAP2p-Y1105-ARHGAP35:RHOA:GTPp-Y1105-ARHGAP35:RASA1BCAR1 p-Y342-PTK6:BCAR1PELP1RHO GTPases ActivateWASPs and WAVEsp-Y88-CDKN1B DOK1UBC(1-76) SemaphorininteractionsADPCCND1 HBEGF(63-148) GPNMBGDP UBA52(1-76) p-Y342-PTK6 HBEGF(63-148) RHOA LRRK2 p-Y342-PTK6DOK1 RHO GTPases activateKTN1UBB(153-228) AKT1EGFR p-Y705-STAT3ADPGDP NRAS HBEGF:EGFR:GPNMBHBEGF:EGFR:p-Y525-GPNMB:LINC01139:p-Y351-PTK6:LRRK2p-Y351-PTK6 NR3C1:DexamethasonePXNPTK6Gene:EPAS1:NR3C1:Dexamethasone:PELP1p-Y705-STAT3dimer:SOCS3 GeneATPSOCS3 GTP KHDRSB3p-Y705-STAT3 CCND1 p-Y88-CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))PIP3 activates AKTsignalingKRAS Phosphorylated p-Y877-ERBB2 heterodimers p-Y342-PTK6:PTPN1PiATPADPDEXA UBB(77-152) PolyUb,p-Y700,Y731,Y774-CBLELMO1 PELP1 p-Y565,S797-HIF1ADEXA NR3C1 ADPCDK2 p-Y31,Y118-PXN:CRK:DOCK180:ELMO1,ELMO2RAF/MAP kinasecascadep-Y435,Y440,Y443-KHDRBS1CDK2 CRK LRRK2 ATPCRK EPAS1 PTK6p-Y342-PTK6 RAC1:GTPp-Y342-PTK6:SOCS3ADPp-Y342-PTK6:PXNPhosphorylated p-6Y-ERBB2 heterodimers UBC(609-684) RHOA:GTPHBEGF:EGFRNR3C1 p-Y250-STAP2 ATPPTK6 NRAS EGFR ATPHIF1A,EPAS1p-Y342,Y447-PTK6p-Y342-PTK6:KHDRBS1PiRHO GTPases activatePKNsADPATPLINC01139 p-Y-KHDRBS2p21 RAS:GTPATPHBEGF(63-148) GTP LINC01139 ATPUbUBC(229-304) KHDRBS1 HRAS p-Y342-PTK6 UBC(533-608) RHO GTPases activatePAKsCCNE1 p-Y250-STAP2 RASA1UBC(153-228) p-Y-SFPQp-Y700,Y731,Y774-CBLEGFR SFPQCDKN1B p-Y-KHDRSB3CDKN1B Signaling by ERBB2EPAS1 ADPp-Y342-PTK6:p-Y250-STAP2:STAT3GTP CDK4 RAC1 ADPGTP p-Y342-PTK6 EGFR RAC1 p21 RAS:GTP:RASA1CDK4 p-Y1105-ARHGAP35 EGFR p21 RAS:GDPKHDRBS1S Phasep-Y1105-ARHGAP35 p-ERBB2heterodimers:PTK6p-Y525-GPNMB PTK6 CRK:DOCK180:ELMO1,ELMO2HIF1AAKT1 RHOA p-Y31,Y118-PXN Phosphorylated p-6Y-ERBB2 heterodimers p-Y315,Y326-AKT1 DOCK1 EPAS1ATPELMO1 CCNE1 CDK2 ATPUBC(457-532) CCND1 PTPN1HRAS ARAP1RHO GTPases ActivateForminsATPp-Y705-STAT3 dimerUBC(77-152) p-ERBB2 heterodimersADPUBC(305-380) RASA1 p-Y342-PTK6 p-Y705-STAT3 dimerSTAT3 SRMSADPSOCS3 Gene p-Y342-PTK6:p-Y315,Y326-AKT1STAT3ELMO2 STAP2 p-Y342-PTK6 GDP RHOA:GDPp-Y342-PTK6:ARAP1GPNMB ATPp-Y705-STAT3 Mitotic G1-G1/SphasesHBEGF(63-148) GTPp-Y342-PTK6:STAP2HIF1A p-Y342-PTK6:DOK1HIF1A RAC1:GDPARHGAP35PXN 17, 52, 69, 94, 108...3, 7, 20, 30, 38...821145, 10, 16, 26, 42...667, 114952, 37, 57, 62, 68...951006363, 15613, 24, 32, 55, 59...95105, 16461, 88, 119, 15111, 34, 91, 96, 107...1022228, 4910154278210514, 25, 39, 44, 113...4, 8, 19, 29, 41...351142231, 43, 79, 143, 15384869511777


PTK6 (BRK) is an oncogenic non-receptor tyrosine kinase that functions downstream of ERBB2 (HER2) (Xiang et al. 2008, Peng et al. 2015) and other receptor tyrosine kinases, such as EGFR (Kamalati et al. 1996) and MET (Castro and Lange 2010). Since ERBB2 forms heterodimers with EGFR and since MET can heterodimerize with both ERBB2 and EGFR (Tanizaki et al. 2011), it is not clear if MET and EGFR activate PTK6 directly or act through ERBB2. Levels of PTK6 increase under hypoxic conditions (Regan Anderson et al. 2013, Pires et al. 2014). The kinase activity of PTK6 is negatively regulated by PTPN1 phosphatase (Fan et al. 2013) and SRMS kinase (Fan et al. 2015), as well as the STAT3 target SOCS3 (Gao et al. 2012).

PTK6 activates STAT3-mediated transcription (Ikeda et al. 2009, Ikeda et al. 2010) and may also activate STAT5-mediated transcription (Ikeda et al. 2011). PTK6 promotes cell motility and migration by regulating the activity of RHO GTPases RAC1 (Chen et al. 2004) and RHOA (Shen et al. 2008), and possibly by affecting motility-related kinesins (Lukong and Richard 2008). PTK6 crosstalks with AKT1 (Zhang et al. 2005, Zheng et al. 2010) and RAS signaling cascades (Shen et al. 2008, Ono et al. 2014) and may be involved in MAPK7 (ERK5) activation (Ostrander et al. 2007, Zheng et al. 2012). PTK6 enhances EGFR signaling by inhibiting EGFR down-regulation (Kang et al. 2010, Li et al. 2012, Kang and Lee 2013). PTK6 may also enhance signaling by IGF1R (Fan et al. 2013) and ERBB3 (Kamalati et al. 2000).<p>PTK6 promotes cell cycle progression by phosphorylating and inactivating CDK inhibitor CDKN1B (p27) (Patel et al. 2015).<p>PTK6 activity is upregulated in osteopontin (OPN or SPP1)-mediated signaling, leading to increased VEGF expression via PTK6/NF-kappaB/ATF4 signaling path. PTK6 may therefore play a role in VEGF-dependent tumor angiogenesis (Chakraborty et al. 2008).<p>PTK6 binds and phosphorylates several nuclear RNA-binding proteins, including SAM68 family members (KHDRSB1, KHDRSB2 and KHDRSB3) (Derry et al. 2000, Haegebarth et al. 2004, Lukong et al. 2005) and SFPQ (PSF) (Lukong et al. 2009). The biological role of PTK6 in RNA processing is not known.<p>For a review of PTK6 function, please refer to Goel and Lukong 2015. View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 8848021
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

Quality Tags

Ontology Terms



View all...
  1. Peng M, Ball-Kell SM, Tyner AL.; ''Protein tyrosine kinase 6 promotes ERBB2-induced mammary gland tumorigenesis in the mouse.''; PubMed
  2. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed
  3. 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
  4. Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR.; ''The E2F transcription factor is a cellular target for the RB protein.''; PubMed
  5. Kovar DR, Harris ES, Mahaffy R, Higgs HN, Pollard TD.; ''Control of the assembly of ATP- and ADP-actin by formins and profilin.''; PubMed
  6. Kang SA, Lee ES, Yoon HY, Randazzo PA, Lee ST.; ''PTK6 inhibits down-regulation of EGF receptor through phosphorylation of ARAP1.''; PubMed
  7. Chong C, Tan L, Lim L, Manser E.; ''The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity.''; PubMed
  8. Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D.; ''The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase.''; PubMed
  9. Castro NE, Lange CA.; ''Breast tumor kinase and extracellular signal-regulated kinase 5 mediate Met receptor signaling to cell migration in breast cancer cells.''; PubMed
  10. Habas R, Kato Y, He X.; ''Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1.''; PubMed
  11. 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
  12. Kamalati T, Jolin HE, Mitchell PJ, Barker KT, Jackson LE, Dean CJ, Page MJ, Gusterson BA, Crompton MR.; ''Brk, a breast tumor-derived non-receptor protein-tyrosine kinase, sensitizes mammary epithelial cells to epidermal growth factor.''; PubMed
  13. 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
  14. Wang S, Watanabe T, Noritake J, Fukata M, Yoshimura T, Itoh N, Harada T, Nakagawa M, Matsuura Y, Arimura N, Kaibuchi K.; ''IQGAP3, a novel effector of Rac1 and Cdc42, regulates neurite outgrowth.''; PubMed
  15. Chakraborty G, Jain S, Kundu GC.; ''Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms.''; PubMed
  16. Miralles F, Posern G, Zaromytidou AI, Treisman R.; ''Actin dynamics control SRF activity by regulation of its coactivator MAL.''; PubMed
  17. Brahimi-Horn MC, Pouysségur J.; ''HIF at a glance.''; PubMed
  18. Ahmadian MR, Kiel C, Stege P, Scheffzek K.; ''Structural fingerprints of the Ras-GTPase activating proteins neurofibromin and p120GAP.''; PubMed
  19. Chittenden T, Livingston DM, Kaelin WG.; ''The T/E1A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA-binding protein.''; PubMed
  20. Chan PM, Manser E.; ''PAKs in human disease.''; PubMed
  21. Li X, Lu Y, Liang K, Hsu JM, Albarracin C, Mills GB, Hung MC, Fan Z.; ''Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR.''; PubMed
  22. Patel P, Asbach B, Shteyn E, Gomez C, Coltoff A, Bhuyan S, Tyner AL, Wagner R, Blain SW.; ''Brk/Protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin D-cyclin-dependent kinase 4.''; PubMed
  23. Haegebarth A, Heap D, Bie W, Derry JJ, Richard S, Tyner AL.; ''The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2.''; PubMed
  24. 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
  25. Brill S, Li S, Lyman CW, Church DM, Wasmuth JJ, Weissbach L, Bernards A, Snijders AJ.; ''The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases.''; PubMed
  26. Yasuda S, Oceguera-Yanez F, Kato T, Okamoto M, Yonemura S, Terada Y, Ishizaki T, Narumiya S.; ''Cdc42 and mDia3 regulate microtubule attachment to kinetochores.''; PubMed
  27. Regan Anderson TM, Peacock DL, Daniel AR, Hubbard GK, Lofgren KA, Girard BJ, Schörg A, Hoogewijs D, Wenger RH, Seagroves TN, Lange CA.; ''Breast tumor kinase (Brk/PTK6) is a mediator of hypoxia-associated breast cancer progression.''; PubMed
  28. Vignal E, Blangy A, Martin M, Gauthier-Rouvière C, Fort P.; ''Kinectin is a key effector of RhoG microtubule-dependent cellular activity.''; PubMed
  29. Hannon GJ, Beach D.; ''p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.''; PubMed
  30. Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L.; ''A brain serine/threonine protein kinase activated by Cdc42 and Rac1.''; PubMed
  31. Dickson BJ.; ''Molecular mechanisms of axon guidance.''; PubMed
  32. 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
  33. Lukong KE, Huot ME, Richard S.; ''BRK phosphorylates PSF promoting its cytoplasmic localization and cell cycle arrest.''; PubMed
  34. Bassi ZI, Audusseau M, Riparbelli MG, Callaini G, D'Avino PP.; ''Citron kinase controls a molecular network required for midbody formation in cytokinesis.''; PubMed
  35. Fan G, Lin G, Lucito R, Tonks NK.; ''Protein-tyrosine phosphatase 1B antagonized signaling by insulin-like growth factor-1 receptor and kinase BRK/PTK6 in ovarian cancer cells.''; PubMed
  36. Kamalati T, Jolin HE, Fry MJ, Crompton MR.; ''Expression of the BRK tyrosine kinase in mammary epithelial cells enhances the coupling of EGF signalling to PI 3-kinase and Akt, via erbB3 phosphorylation.''; PubMed
  37. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed
  38. 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
  39. Fukata M, Kuroda S, Fujii K, Nakamura T, Shoji I, Matsuura Y, Okawa K, Iwamatsu A, Kikuchi A, Kaibuchi K.; ''Regulation of cross-linking of actin filament by IQGAP1, a target for Cdc42.''; PubMed
  40. Chastkofsky MI, Bie W, Ball-Kell SM, He YY, Tyner AL.; ''Protein Tyrosine Kinase 6 Regulates UVB-Induced Signaling and Tumorigenesis in Mouse Skin.''; PubMed
  41. Connell-Crowley L, Harper JW, Goodrich DW.; ''Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation.''; PubMed
  42. Lammers M, Rose R, Scrima A, Wittinghofer A.; ''The regulation of mDia1 by autoinhibition and its release by Rho*GTP.''; PubMed
  43. Pasterkamp RJ, Kolodkin AL.; ''Semaphorin junction: making tracks toward neural connectivity.''; PubMed
  44. Pelikan-Conchaudron A, Le Clainche C, Didry D, Carlier MF.; ''The IQGAP1 protein is a calmodulin-regulated barbed end capper of actin filaments: possible implications in its function in cell migration.''; PubMed
  45. Wallar BJ, Deward AD, Resau JH, Alberts AS.; ''RhoB and the mammalian Diaphanous-related formin mDia2 in endosome trafficking.''; PubMed
  46. Liu L, Gao Y, Qiu H, Miller WT, Poli V, Reich NC.; ''Identification of STAT3 as a specific substrate of breast tumor kinase.''; PubMed
  47. Ono H, Basson MD, Ito H.; ''PTK6 promotes cancer migration and invasion in pancreatic cancer cells dependent on ERK signaling.''; PubMed
  48. Serrano M, Hannon GJ, Beach D.; ''A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.''; PubMed
  49. Hotta K, Tanaka K, Mino A, Kohno H, Takai Y.; ''Interaction of the Rho family small G proteins with kinectin, an anchoring protein of kinesin motor.''; PubMed
  50. Parry D, Bates S, Mann DJ, Peters G.; ''Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product.''; PubMed
  51. Holinstat M, Knezevic N, Broman M, Samarel AM, Malik AB, Mehta D.; ''Suppression of RhoA activity by focal adhesion kinase-induced activation of p190RhoGAP: role in regulation of endothelial permeability.''; PubMed
  52. Majmundar AJ, Wong WJ, Simon MC.; ''Hypoxia-inducible factors and the response to hypoxic stress.''; PubMed
  53. Bione S, Sala C, Manzini C, Arrigo G, Zuffardi O, Banfi S, Borsani G, Jonveaux P, Philippe C, Zuccotti M, Ballabio A, Toniolo D.; ''A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications for human sterility.''; PubMed
  54. Derry JJ, Richard S, Valderrama Carvajal H, Ye X, Vasioukhin V, Cochrane AW, Chen T, Tyner AL.; ''Sik (BRK) phosphorylates Sam68 in the nucleus and negatively regulates its RNA binding ability.''; PubMed
  55. 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
  56. Szczepanowska J.; ''Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements.''; PubMed
  57. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed
  58. Colón-Franco JM, Gomez TS, Billadeau DD.; ''Dynamic remodeling of the actin cytoskeleton by FMNL1γ is required for structural maintenance of the Golgi complex.''; PubMed
  59. 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
  60. Vidal A, Koff A.; ''Cell-cycle inhibitors: three families united by a common cause.''; PubMed
  61. Wells A.; ''EGF receptor.''; PubMed
  62. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed
  63. Ikeda O, Miyasaka Y, Sekine Y, Mizushima A, Muromoto R, Nanbo A, Yoshimura A, Matsuda T.; ''STAP-2 is phosphorylated at tyrosine-250 by Brk and modulates Brk-mediated STAT3 activation.''; PubMed
  64. 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
  65. 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
  66. Jung JH, Traugh JA.; ''Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141.''; PubMed
  67. Li R, Zhang B, Zheng Y.; ''Structural determinants required for the interaction between Rho GTPase and the GTPase-activating domain of p190.''; PubMed
  68. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed
  69. Nizet V, Johnson RS.; ''Interdependence of hypoxic and innate immune responses.''; PubMed
  70. King PD, Lubeck BA, Lapinski PE.; ''Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis.''; PubMed
  71. Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K.; ''The retinoblastoma protein binds to a family of E2F transcription factors.''; PubMed
  72. Fernandez-Borja M, Janssen L, Verwoerd D, Hordijk P, Neefjes J.; ''RhoB regulates endosome transport by promoting actin assembly on endosomal membranes through Dia1.''; PubMed
  73. 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
  74. Li F, Higgs HN.; ''The mouse Formin mDia1 is a potent actin nucleation factor regulated by autoinhibition.''; PubMed
  75. Kühn S, Geyer M.; ''Formins as effector proteins of Rho GTPases.''; PubMed
  76. 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
  77. Gao Y, Cimica V, Reich NC.; ''Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3.''; PubMed
  78. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed
  79. Koncina E, Roth L, Gonthier B, Bagnard D.; ''Role of semaphorins during axon growth and guidance.''; PubMed
  80. Ikeda O, Mizushima A, Sekine Y, Yamamoto C, Muromoto R, Nanbo A, Oritani K, Yoshimura A, Matsuda T.; ''Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells.''; PubMed
  81. Zhang B, Chernoff J, Zheng Y.; ''Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA.''; PubMed
  82. Chen HY, Shen CH, Tsai YT, Lin FC, Huang YP, Chen RH.; ''Brk activates rac1 and promotes cell migration and invasion by phosphorylating paxillin.''; PubMed
  83. Pires IM, Blokland NJ, Broos AW, Poujade FA, Senra JM, Eccles SA, Span PN, Harvey AJ, Hammond EM.; ''HIF-1α-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion.''; PubMed
  84. Yang J, Huang J, Dasgupta M, Sears N, Miyagi M, Wang B, Chance MR, Chen X, Du Y, Wang Y, An L, Wang Q, Lu T, Zhang X, Wang Z, Stark GR.; ''Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes.''; PubMed
  85. Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y.; ''Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.''; PubMed
  86. Lane J, Martin T, Weeks HP, Jiang WG.; ''Structure and role of WASP and WAVE in Rho GTPase signalling in cancer.''; PubMed
  87. Zhang H.; ''Life without kinase: cyclin E promotes DNA replication licensing and beyond.''; PubMed
  88. Carpenter G.; ''Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways.''; PubMed
  89. Tominaga T, Sahai E, Chardin P, McCormick F, Courtneidge SA, Alberts AS.; ''Diaphanous-related formins bridge Rho GTPase and Src tyrosine kinase signaling.''; PubMed
  90. Xu Y, Moseley JB, Sagot I, Poy F, Pellman D, Goode BL, Eck MJ.; ''Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture.''; PubMed
  91. Zhang W, Benson DL.; ''Targeting and clustering citron to synapses.''; PubMed
  92. Scheffzek K, Ahmadian MR, Kabsch W, Wiesmüller L, Lautwein A, Schmitz F, Wittinghofer A.; ''The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants.''; PubMed
  93. Cobrinik D.; ''Pocket proteins and cell cycle control.''; PubMed
  94. Semenza GL.; ''Life with oxygen.''; PubMed
  95. Lin A, Li C, Xing Z, Hu Q, Liang K, Han L, Wang C, Hawke DH, Wang S, Zhang Y, Wei Y, Ma G, Park PK, Zhou J, Zhou Y, Hu Z, Zhou Y, Marks JR, Liang H, Hung MC, Lin C, Yang L.; ''The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.''; PubMed
  96. 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
  97. Depoortere F, Van Keymeulen A, Lukas J, Costagliola S, Bartkova J, Dumont JE, Bartek J, Roger PP, Dremier S.; ''A requirement for cyclin D3-cyclin-dependent kinase (cdk)-4 assembly in the cyclic adenosine monophosphate-dependent proliferation of thyrocytes.''; PubMed
  98. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed
  99. Ahmadian MR, Stege P, Scheffzek K, Wittinghofer A.; ''Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras.''; PubMed
  100. Regan Anderson TM, Ma SH, Raj GV, Cidlowski JA, Helle TM, Knutson TP, Krutilina RI, Seagroves TN, Lange CA.; ''Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer.''; PubMed
  101. Xiang B, Chatti K, Qiu H, Lakshmi B, Krasnitz A, Hicks J, Yu M, Miller WT, Muthuswamy SK.; ''Brk is coamplified with ErbB2 to promote proliferation in breast cancer.''; PubMed
  102. Miah S, Goel RK, Dai C, Kalra N, Beaton-Brown E, Bagu ET, Bonham K, Lukong KE.; ''BRK targets Dok1 for ubiquitin-mediated proteasomal degradation to promote cell proliferation and migration.''; PubMed
  103. Isobe A, Takeda T, Sakata M, Yamamoto T, Minekawa R, Hayashi M, Auernhammer CJ, Tasaka K, Murata Y.; ''STAT3-mediated constitutive expression of SOCS3 in an undifferentiated rat trophoblast-like cell line.''; PubMed
  104. Kang SA, Lee ST.; ''PTK6 promotes degradation of c-Cbl through PTK6-mediated phosphorylation.''; PubMed
  105. Zheng Y, Peng M, Wang Z, Asara JM, Tyner AL.; ''Protein tyrosine kinase 6 directly phosphorylates AKT and promotes AKT activation in response to epidermal growth factor.''; PubMed
  106. 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
  107. Watanabe S, De Zan T, Ishizaki T, Narumiya S.; ''Citron kinase mediates transition from constriction to abscission through its coiled-coil domain.''; PubMed
  108. Loenarz C, Schofield CJ.; ''Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases.''; PubMed
  109. Goel RK, Lukong KE.; ''Tracing the footprints of the breast cancer oncogene BRK - Past till present.''; PubMed
  110. Yayoshi-Yamamoto S, Taniuchi I, Watanabe T.; ''FRL, a novel formin-related protein, binds to Rac and regulates cell motility and survival of macrophages.''; PubMed
  111. Mukai H, Toshimori M, Shibata H, Takanaga H, Kitagawa M, Miyahara M, Shimakawa M, Ono Y.; ''Interaction of PKN with alpha-actinin.''; PubMed
  112. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed
  113. Kuroda S, Fukata M, Kobayashi K, Nakafuku M, Nomura N, Iwamatsu A, Kaibuchi K.; ''Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1.''; PubMed
  114. Shen CH, Chen HY, Lin MS, Li FY, Chang CC, Kuo ML, Settleman J, Chen RH.; ''Breast tumor kinase phosphorylates p190RhoGAP to regulate rho and ras and promote breast carcinoma growth, migration, and invasion.''; PubMed
  115. Tian YM, Yeoh KK, Lee MK, Eriksson T, Kessler BM, Kramer HB, Edelmann MJ, Willam C, Pugh CW, Schofield CJ, Ratcliffe PJ.; ''Differential sensitivity of hypoxia inducible factor hydroxylation sites to hypoxia and hydroxylase inhibitors.''; PubMed
  116. Vega FM, Fruhwirth G, Ng T, Ridley AJ.; ''RhoA and RhoC have distinct roles in migration and invasion by acting through different targets.''; PubMed
  117. Zheng Y, Asara JM, Tyner AL.; ''Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 CRK-associated substrate.''; PubMed
  118. 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
  119. Schlessinger J.; ''Ligand-induced, receptor-mediated dimerization and activation of EGF receptor.''; PubMed
  120. White CD, Erdemir HH, Sacks DB.; ''IQGAP1 and its binding proteins control diverse biological functions.''; PubMed
  121. Wiejak J, Dunlop J, Gao S, Borland G, Yarwood SJ.; ''Extracellular signal-regulated kinase mitogen-activated protein kinase-dependent SOCS-3 gene induction requires c-Jun, signal transducer and activator of transcription 3, and specificity protein 3 transcription factors.''; PubMed
  122. Lukong KE, Larocque D, Tyner AL, Richard S.; ''Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression.''; PubMed
  123. 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
  124. Serres MP, Kossatz U, Chi Y, Roberts JM, Malek NP, Besson A.; ''p27(Kip1) controls cytokinesis via the regulation of citron kinase activation.''; PubMed
  125. Kitzing TM, Wang Y, Pertz O, Copeland JW, Grosse R.; ''Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC.''; PubMed
  126. Daniels RH, Bokoch GM.; ''p21-activated protein kinase: a crucial component of morphological signaling?''; PubMed
  127. Hutchinson CL, Lowe PN, McLaughlin SH, Mott HR, Owen D.; ''Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1.''; PubMed
  128. Bashour AM, Fullerton AT, Hart MJ, Bloom GS.; ''IQGAP1, a Rac- and Cdc42-binding protein, directly binds and cross-links microfilaments.''; PubMed
  129. Pouysségur J, Dayan F, Mazure NM.; ''Hypoxia signalling in cancer and approaches to enforce tumour regression.''; PubMed
  130. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed
  131. Coyle JH, Guzik BW, Bor YC, Jin L, Eisner-Smerage L, Taylor SJ, Rekosh D, Hammarskjöld ML.; ''Sam68 enhances the cytoplasmic utilization of intron-containing RNA and is functionally regulated by the nuclear kinase Sik/BRK.''; PubMed
  132. Sadasivam S, DeCaprio JA.; ''The DREAM complex: master coordinator of cell cycle-dependent gene expression.''; PubMed
  133. Cheng M, Sexl V, Sherr CJ, Roussel MF.; ''Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).''; PubMed
  134. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed
  135. Swart-Mataraza JM, Li Z, Sacks DB.; ''IQGAP1 is a component of Cdc42 signaling to the cytoskeleton.''; PubMed
  136. 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
  137. Parrini MC, Lei M, Harrison SC, Mayer BJ.; ''Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1.''; PubMed
  138. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed
  139. Guan KL, Jenkins CW, Li Y, O'Keefe CL, Noh S, Wu X, Zariwala M, Matera AG, Xiong Y.; ''Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4.''; PubMed
  140. Fan G, Aleem S, Yang M, Miller WT, Tonks NK.; ''Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase.''; PubMed
  141. Bagchi S, Weinmann R, Raychaudhuri P.; ''The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F.''; PubMed
  142. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed
  143. Pasterkamp RJ, Verhaagen J.; ''Semaphorins in axon regeneration: developmental guidance molecules gone wrong?''; PubMed
  144. 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
  145. Ikeda O, Sekine Y, Mizushima A, Nakasuji M, Miyasaka Y, Yamamoto C, Muromoto R, Nanbo A, Oritani K, Yoshimura A, Matsuda T.; ''Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells.''; PubMed
  146. Ostrander JH, Daniel AR, Lofgren K, Kleer CG, Lange CA.; ''Breast tumor kinase (protein tyrosine kinase 6) regulates heregulin-induced activation of ERK5 and p38 MAP kinases in breast cancer cells.''; PubMed
  147. 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
  148. Seth A, Otomo C, Rosen MK.; ''Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLalpha and mDia1.''; PubMed
  149. 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
  150. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed
  151. Herbst RS.; ''Review of epidermal growth factor receptor biology.''; PubMed
  152. Gasman S, Kalaidzidis Y, Zerial M.; ''RhoD regulates endosome dynamics through Diaphanous-related Formin and Src tyrosine kinase.''; PubMed
  153. Zhou Y, Gunput RA, Pasterkamp RJ.; ''Semaphorin signaling: progress made and promises ahead.''; PubMed
  154. Kato T, Gotoh Y, Hoffmann A, Ono Y.; ''Negative regulation of constitutive NF-kappaB and JNK signaling by PKN1-mediated phosphorylation of TRAF1.''; PubMed
  155. Kaelin WG, Ratcliffe PJ.; ''Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.''; PubMed
  156. Minoguchi M, Minoguchi S, Aki D, Joo A, Yamamoto T, Yumioka T, Matsuda T, Yoshimura A.; ''STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif.''; PubMed
  157. Lukong KE, Richard S.; ''Breast tumor kinase BRK requires kinesin-2 subunit KAP3A in modulation of cell migration.''; PubMed
  158. Nezami AG, Poy F, Eck MJ.; ''Structure of the autoinhibitory switch in formin mDia1.''; PubMed
  159. Tanizaki J, Okamoto I, Sakai K, Nakagawa K.; ''Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification.''; PubMed
  160. 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
  161. Romero S, Le Clainche C, Didry D, Egile C, Pantaloni D, Carlier MF.; ''Formin is a processive motor that requires profilin to accelerate actin assembly and associated ATP hydrolysis.''; PubMed
  162. Fan L, Pellegrin S, Scott A, Mellor H.; ''The small GTPase Rif is an alternative trigger for the formation of actin stress fibers in epithelial cells.''; PubMed
  163. Cheng L, Zhang J, Ahmad S, Rozier L, Yu H, Deng H, Mao Y.; ''Aurora B regulates formin mDia3 in achieving metaphase chromosome alignment.''; PubMed
  164. Zhang P, Ostrander JH, Faivre EJ, Olsen A, Fitzsimmons D, Lange CA.; ''Regulated association of protein kinase B/Akt with breast tumor kinase.''; PubMed
  165. Wu L, Timmers C, Maiti B, Saavedra HI, Sang L, Chong GT, Nuckolls F, Giangrande P, Wright FA, Field SJ, Greenberg ME, Orkin S, Nevins JR, Robinson ML, Leone G.; ''The E2F1-3 transcription factors are essential for cellular proliferation.''; PubMed
  166. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed
  167. Hiebert SW.; ''Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression.''; PubMed
  168. 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


View all...
102035view16:22, 26 November 2018Marvin M2Ontology Term : 'PW:0000003' removed !
102034view16:21, 26 November 2018Marvin M2Ontology Term : 'kinase mediated signaling pathway' added !
101698view14:35, 1 November 2018DeSlOntology Term : 'signaling pathway' added !
101490view11:35, 1 November 2018ReactomeTeamreactome version 66
101027view21:15, 31 October 2018ReactomeTeamreactome version 65
100725view20:11, 31 October 2018ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AKT1 ProteinP31749 (Uniprot-TrEMBL)
AKT1ProteinP31749 (Uniprot-TrEMBL)
ARAP1 ProteinQ96P48 (Uniprot-TrEMBL)
ARAP1ProteinQ96P48 (Uniprot-TrEMBL)
ARHGAP35 ProteinQ9NRY4 (Uniprot-TrEMBL)
ARHGAP35ProteinQ9NRY4 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BCAR1 ProteinP56945 (Uniprot-TrEMBL)
BCAR1ProteinP56945 (Uniprot-TrEMBL)
CBLProteinP22681 (Uniprot-TrEMBL)
CCND1 ProteinP24385 (Uniprot-TrEMBL)
CCNE1 ProteinP24864 (Uniprot-TrEMBL)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDK4 ProteinP11802 (Uniprot-TrEMBL)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ComplexR-HSA-8848419 (Reactome)
CRK ProteinP46108 (Uniprot-TrEMBL)
CRK:DOCK180:ELMO1,ELMO2ComplexR-HSA-2029141 (Reactome)
DEXA MetaboliteCHEBI:41879 (ChEBI)
DOCK1 ProteinQ14185 (Uniprot-TrEMBL)
DOK1 ProteinQ99704 (Uniprot-TrEMBL)
DOK1ProteinQ99704 (Uniprot-TrEMBL)
EGFR ProteinP00533 (Uniprot-TrEMBL)
ELMO1 ProteinQ92556 (Uniprot-TrEMBL)
ELMO2 ProteinQ96JJ3 (Uniprot-TrEMBL)
EPAS1 ProteinQ99814 (Uniprot-TrEMBL)
EPAS1ProteinQ99814 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GPNMB ProteinQ14956 (Uniprot-TrEMBL)
GPNMBProteinQ14956 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HBEGF(63-148) ProteinQ99075 (Uniprot-TrEMBL)
HBEGF:EGFR:GPNMBComplexR-HSA-8857546 (Reactome)
HBEGF:EGFR:p-Y525-GPNMB:LINC01139:PTK6:LRRK2ComplexR-HSA-8857567 (Reactome)
HBEGF:EGFR:p-Y525-GPNMB:LINC01139:p-Y351-PTK6:LRRK2ComplexR-HSA-8857574 (Reactome)
HBEGF:EGFR:p-Y525-GPNMBComplexR-HSA-8857556 (Reactome)
HBEGF:EGFRComplexR-HSA-8857547 (Reactome)
HIF1A ProteinQ16665 (Uniprot-TrEMBL)
HIF1A,EPAS1:PTK6 GeneComplexR-HSA-8848808 (Reactome)
HIF1A,EPAS1ComplexR-HSA-8848802 (Reactome)
HIF1AProteinQ16665 (Uniprot-TrEMBL)
HRAS ProteinP01112 (Uniprot-TrEMBL)
KHDRBS1 ProteinQ07666 (Uniprot-TrEMBL)
KHDRBS1ProteinQ07666 (Uniprot-TrEMBL)
KHDRBS2ProteinQ5VWX1 (Uniprot-TrEMBL)
KHDRSB3ProteinO75525 (Uniprot-TrEMBL)
KRAS ProteinP01116 (Uniprot-TrEMBL)
LINC01139 ProteinENST00000400946 (Ensembl)
LINC01139RnaENST00000400946 (Ensembl)
LRRK2 ProteinQ5S007 (Uniprot-TrEMBL)
LRRK2ProteinQ5S007 (Uniprot-TrEMBL)
Mitotic G1-G1/S phasesPathwayR-HSA-453279 (Reactome) Mitotic G1-G1/S phase involves G1 phase of the mitotic interphase and G1/S transition, when a cell commits to DNA replication and divison genetic and cellular material to two daughter cells.

During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).

During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.

NR3C1 ProteinP04150 (Uniprot-TrEMBL)
NR3C1:DexamethasoneComplexR-HSA-879850 (Reactome)
NRAS ProteinP01111 (Uniprot-TrEMBL)
PELP1 ProteinQ8IZL8 (Uniprot-TrEMBL)
PELP1ProteinQ8IZL8 (Uniprot-TrEMBL)
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.
PTK6 Gene:EPAS1:NR3C1:Dexamethasone:PELP1ComplexR-HSA-8856931 (Reactome)
PTK6 Gene ProteinENSG00000101213 (Ensembl)
PTK6 GeneGeneProductENSG00000101213 (Ensembl)
PTK6 ProteinQ13882 (Uniprot-TrEMBL)
PTK6ProteinQ13882 (Uniprot-TrEMBL)
PTPN1 ProteinP18031 (Uniprot-TrEMBL)
PTPN1ProteinP18031 (Uniprot-TrEMBL)
PXN ProteinP49023 (Uniprot-TrEMBL)
PXNProteinP49023 (Uniprot-TrEMBL)
Phosphorylated p-6Y-ERBB2 heterodimers R-HSA-1963585 (Reactome)
Phosphorylated p-Y877-ERBB2 heterodimers R-HSA-1963580 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
PolyUb,p-Y700,Y731,Y774-CBLProteinP22681 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GDPComplexR-HSA-5674631 (Reactome)
RAC1:GTPComplexR-HSA-442641 (Reactome)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RASA1 ProteinP20936 (Uniprot-TrEMBL)
RASA1ProteinP20936 (Uniprot-TrEMBL)
RHO GTPases Activate ForminsPathwayR-HSA-5663220 (Reactome) Formins are a family of proteins with 15 members in mammals, organized into 8 subfamilies. Formins are involved in the regulation of actin cytoskeleton. Many but not all formin family members are activated by RHO GTPases. Formins that serve as effectors of RHO GTPases belong to different formin subfamilies but they all share a structural similarity to Drosophila protein diaphanous and are hence named diaphanous-related formins (DRFs).

DRFs activated by RHO GTPases contain a GTPase binding domain (GBD) at their N-terminus, followed by formin homology domains 3, 1, and 2 (FH3, FH1, FH2) and a diaphanous autoregulatory domain (DAD) at the C-terminus. Most DRFs contain a dimerization domain (DD) and a coiled-coil region (CC) in between FH3 and FH1 domains (reviewed by Kuhn and Geyer 2014). RHO GTPase-activated DRFs are autoinhibited through the interaction between FH3 and DAD which is disrupted upon binding to an active RHO GTPase (Li and Higgs 2003, Lammers et al. 2005, Nezami et al. 2006). Since formins dimerize, it is not clear whether the FH3-DAD interaction is intra- or intermolecular. FH2 domain is responsible for binding to the F-actin and contributes to the formation of head-to-tail formin dimers (Xu et al. 2004). The proline-rich FH1 domain interacts with the actin-binding proteins profilins, thereby facilitating actin recruitment to formins and accelerating actin polymerization (Romero et al. 2004, Kovar et al. 2006).

Different formins are activated by different RHO GTPases in different cell contexts. FMNL1 (formin-like protein 1) is activated by binding to the RAC1:GTP and is involved in the formation of lamellipodia in macrophages (Yayoshi-Yamamoto et al. 2000) and is involved in the regulation of the Golgi complex structure (Colon-Franco et al. 2011). Activation of FMNL1 by CDC42:GTP contributes to the formation of the phagocytic cup (Seth et al. 2006). Activation of FMNL2 (formin-like protein 2) and FMNL3 (formin-like protein 3) by RHOC:GTP is involved in cancer cell motility and invasiveness (Kitzing et al. 2010, Vega et al. 2011). DIAPH1, activated by RHOA:GTP, promotes elongation of actin filaments and activation of SRF-mediated transcription which is inhibited by unpolymerized actin (Miralles et al. 2003). RHOF-mediated activation of DIAPH1 is implicated in formation of stress fibers (Fan et al. 2010). Activation of DIAPH1 and DIAPH3 by RHOB:GTP leads to actin coat formation around endosomes and regulates endosome motility and trafficking (Fernandez-Borja et al. 2005, Wallar et al. 2007). Endosome trafficking is also regulated by DIAPH2 transcription isoform 3 (DIAPH2-3) which, upon activation by RHOD:GTP, recruits SRC kinase to endosomes (Tominaga et al. 2000, Gasman et al. 2003). DIAPH2 transcription isoform 2 (DIAPH2-2) is involved in mitosis where, upon being activated by CDC42:GTP, it facilitates the capture of astral micr