Epidermal Growth Factor-dependent Regulation of Cdc42 Is Mediated by the Src Tyrosine Kinase

Tu, S. Sean; Wu, Wen Jin; Wang, Jiabin; Cerione, Richard A.

doi:10.1074/jbc.m307021200

Cited by 102 publications

(99 citation statements)

References 46 publications

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“…Moreover, in response to growth factors in other cell types, tyrosine phosphorylation of ␤Pix at tyrosine 442 by SFKs is required for its GEF abilities and subsequent activation of Cdc42 (23,24). Furthermore, Cdc42 itself has been suggested to undergo tyrosine phosphorylation in COS-7 cells (41). In this manner it is conceivable that YES kinase activation could ignite additional activation events centered at the Cdc42 signaling node.…”

Section: Discussionmentioning

confidence: 99%

YES, a Src Family Kinase, Is a Proximal Glucose-specific Activator of Cell Division Cycle Control Protein 42 (Cdc42) in Pancreatic Islet β Cells

Yoder

Dineen

Wang

et al. 2014

Journal of Biological Chemistry

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Background: Although Cdc42 signaling is a known requirement for insulin secretion to occur, how it is initiated remains unknown. Results: YES kinase is required for Cdc42 activation in human islets and ␤ cells. Conclusion: YES is a proximal, glucose-specific activator of Cdc42 and glucose-simulated insulin secretion. Significance: YES may provide a novel target for improvement of functional ␤ cell mass.

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Section: Discussionmentioning

confidence: 99%

YES, a Src Family Kinase, Is a Proximal Glucose-specific Activator of Cell Division Cycle Control Protein 42 (Cdc42) in Pancreatic Islet β Cells

Yoder

Dineen

Wang

et al. 2014

Journal of Biological Chemistry

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“…Recent work from Mann and colleagues (45) identified phosphorylation by LRRK2 of the switch II regions of Rab3a, Rab8a, Rab10, and Rab12 as a driver of membrane localization. In addition, a few GTPases outside the Rab family, including Cdc42, Rac1, and Ran, are thought to be regulated by modification of switch II (46)(47)(48). Switch II has long been recognized for its importance in dictating the Rab activation state; it has now becoming clear that posttranslational modification of this region allows further, external control of Rab function.…”

Section: Discussionmentioning

confidence: 99%

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

Levin

Hertz

Burlingame

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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TGF-β activated kinase 1 (TAK1) is a critical signaling hub responsible for translating antigen binding signals to immune receptors for the activation of the AP-1 and NF-κB master transcriptional programs. Despite its importance, known substrates of TAK1 are limited to kinases of the MAPK and IKK families and include no direct effectors of biochemical processes. Here, we identify over 200 substrates of TAK1 using a chemical genetic kinase strategy. We validate phosphorylation of the dynamic switch II region of GTPase Rab1, a mediator of endoplasmic reticulum to Golgi vesicular transport, at T75 to be regulated by TAK1 in vivo. TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPaseactivating protein (GAP) enzymes, and is exclusive to membranelocalized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. Previous studies established that the pathogen Legionella pneumophila is capable of hijacking Rab1 function through posttranslational modifications of the switch II region. Here, we present evidence that Rab1 is regulated by the host in a similar fashion, and that the innate immunity kinase TAK1 and Legionella effectors compete to regulate Rab1 by switch II modifications during infection.

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Section: Introductionmentioning

confidence: 99%

“…The p21 GTPases themselves are regulated by guanine nucleotide exchange factors (GEFs) that turn them on, GTPase activating proteins (GAPs) that turn them off, and guanine nucleotide dissociation inhibitors that can function as sequestering agents (Suetsugu and Takenawa, 2003;Burridge and Wennerberg, 2004;Raftopoulou and Hall, 2004). The activities of many of these proteins have been found to be regulated by FAK and Src-family kinases (Hildebrand et al, 1996;Han et al, 1997;Kiyono et al, 2000;Haskell et al, 2001;Tu et al, 2003;Zhai et al, 2003;Stacey et al, 2004).The pathways of activation and signaling from the p21-activated protein kinase (PAK) typify the sophisticated mechanisms developed by cells to respond to extracellular cues (Bokoch, 2003). In response to cell attachment and/or growth factor stimulation, PAK is activated and signals to Galisteo et al, 1996;Lu et al, 1997;Sells et al, 1997;Kiosses et al, 2002), the Cdc42/Rac GEF PIX (Bagrodia et al, 1998;Zhao et al, 2000a), the paxillin kinase linker (PKL)/G protein-coupled receptor kinase-interacting protein (GIT) family of ArfGAPs Premont et al, 2000;Brown et al, 2002;Manabe Ri et al, 2002), and the molecular scaffold protein paxillin Zhao et al, 2000b;Hashimoto et al, 2001;West et al, 2001;Brown et al, 2002).…”

mentioning

confidence: 99%

Src and FAK Kinases Cooperate to Phosphorylate Paxillin Kinase Linker, Stimulate Its Focal Adhesion Localization, and Regulate Cell Spreading and Protrusiveness

Brown

Cary

Jamieson

et al. 2005

MBoC

167

179

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The ArfGAP paxillin kinase linker (PKL)/G protein-coupled receptor kinase-interacting protein (GIT)2 has been implicated in regulating cell spreading and motility through its transient recruitment of the p21-activated kinase (PAK) to focal adhesions. The Nck-PAK-PIX-PKL protein complex is recruited to focal adhesions by paxillin upon integrin engagement and Rac activation. In this report, we identify tyrosine-phosphorylated PKL as a protein that associates with the SH3-SH2 adaptor Nck, in a Src-dependent manner, after cell adhesion to fibronectin. Both cell adhesion and Rac activation stimulated PKL tyrosine phosphorylation. PKL is phosphorylated on tyrosine residues 286/392/592 by Src and/or FAK and these sites are required for PKL localization to focal adhesions and for paxillin binding. The absence of either FAK or Src-family kinases prevents PKL phosphorylation and suppresses localization of PKL but not GIT1 to focal adhesions after Rac activation. Expression of an activated FAK mutant in the absence of Src-family kinases partially restores PKL localization, suggesting that Src activation of FAK is required for PKL phosphorylation and localization. Overexpression of the nonphosphorylated GFP-PKL Triple YF mutant stimulates cell spreading and protrusiveness, similar to overexpression of a paxillin mutant that does not bind PKL, suggesting that failure to recruit PKL to focal adhesions interferes with normal cell spreading and motility. INTRODUCTIONCell attachment, spreading, and motility are complex processes requiring the integration of diverse signaling networks and structural assemblies (Jockusch et al., 1995;Sastry and Burridge, 2000;Juliano, 2002). One of the earliest steps in transducing extracellular cues through integrins to the cytoskeleton is the activation of the tyrosine kinases Src and FAK (Schwartz et al., 1995;Giancotti and Tarone, 2003). FAK is an integrin-binding nonreceptor tyrosine kinase that upon integrin ligation is activated to autophosphorylate Y397 and bind to the Src SH2 domain (Schaller et al., 1994;Calalb et al., 1995). Src then phosphorylates FAK on multiple residues that increase FAK kinase activity and several downstream binding partners for Src/FAK are targeted for phosphorylation, including the focal adhesion proteins p130Cas and paxillin (reviewed in Brown and Turner, 2004;Playford and Schaller, 2004;Mitra et al., 2005). Phosphorylated paxillin binding to the SH2/SH3 adaptor protein Crk is implicated in Rac activation and stimulation of cell motility (Petit et al., 2000;Lamorte et al., 2003;Valles et al., 2004), whereas binding of paxillin to the p120RasGAP SH2 domain may displace and allow for the activation of p190RhoGAP and subsequent decrease in RhoA activity (Iwasaki et al., 2002).The Cdc42, Rac1, and RhoA members of the Ras superfamily of p21 GTPases are central intermediaries in coordinating the defined temporal-spatial progression of signals emanating from initial integrin ligation, through acquisition of a polarized state, to initiation and maintenance of directed ce...

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Epidermal Growth Factor-dependent Regulation of Cdc42 Is Mediated by the Src Tyrosine Kinase

Cited by 102 publications

References 46 publications

YES, a Src Family Kinase, Is a Proximal Glucose-specific Activator of Cell Division Cycle Control Protein 42 (Cdc42) in Pancreatic Islet β Cells

YES, a Src Family Kinase, Is a Proximal Glucose-specific Activator of Cell Division Cycle Control Protein 42 (Cdc42) in Pancreatic Islet β Cells

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

Src and FAK Kinases Cooperate to Phosphorylate Paxillin Kinase Linker, Stimulate Its Focal Adhesion Localization, and Regulate Cell Spreading and Protrusiveness

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