ERK Regulates the Hepatocyte Growth Factor-mediated Interaction of Gab1 and the Phosphatidylinositol 3-Kinase

Yu, Cui; Roshan, Bijan; Liu, Zhenxiang; Cantley, Lloyd G.

doi:10.1074/jbc.m104493200

Cited by 56 publications

(47 citation statements)

References 37 publications

(45 reference statements)

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“…Thus, ERK1/2-mediated phosphorylation of this site can initiate a novel regulation of the Gab1/PI3K interaction. This was confirmed by demonstrating that HGF-stimulated association of the PI3K with Gab1 was partially dependent on ERK activation (7).…”

supporting

confidence: 66%

“…Structural and functional studies suggest that Gab1 is a multisubstratedocking protein functioning downstream of several receptor signaling pathways including the epidermal growth factor (EGF) receptor (EGFR), c-met, and the insulin receptor tyrosine kinases as well as cytokine receptors such as the gp130-associated interleukin-6 receptor and T and B cell antigen receptors (7)(8)(9)(10). Similar to the Drosophila daughter of sevenless protein, DOS, and the insulin receptor substrate proteins 1 and 2 family, Gab1 consists of a PH domain at its N terminus, several proline-rich motifs in the C-terminus, and multiple tyrosine phosphorylation sites.…”

mentioning

confidence: 99%

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ERK Negatively Regulates the Epidermal Growth Factor-mediated Interaction of Gab1 and the Phosphatidylinositol 3-Kinase

Liu

Cantley

2002

Journal of Biological Chemistry

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126

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We have examined the ability of epidermal growth factor (EGF)-stimulated ERK activation to regulate Grb2-associated binder-1 (Gab1)/phosphatidylinositol 3-kinase (PI3K) interactions. Inhibiting ERK activation with the MEK inhibitor U0126 increased the EGF-stimulated association of Gab1 with either full-length glutathione S-transferase-p85 or the p85 C-terminal Src homology 2 (SH2) domain, a result reproduced by coimmunoprecipitation of the native proteins from intact cells. This increased association of Gab1 and the PI3K correlates with an increase in PI3K activity and greater phosphorylation of Akt. This result is in direct contrast to what we have previously reported following HGF stimulation where MEK inhibition decreased the HGFstimulated association of Gab1 and p85. In support of this divergent effect of ERK on Gab1/PI3K association following HGF and EGF stimulation, U0126 decreased the HGF-stimulated association of p85 and the Gab1 c-Met binding domain but did not alter the EGF-stimulated association of p85 and the c-Met binding domain. An examination of the mechanism of this effect revealed that the treatment of cells with EGF ؉ U0126 increased the tyrosine phosphorylation of Gab1 as well as its association with another SH2-containing protein, SHP2. Furthermore, overexpression of a catalytically inactive form of SHP2 or pretreatment with pervanadate markedly increased EGF-stimulated Gab1 tyrosine phosphorylation. These experiments demonstrate that EGF and HGF-mediated ERK activation result in divergent effects on Gab1/PI3K signaling. HGF-stimulated ERK activation increases the Gab1/PI3K association, whereas EGF-stimulated ERK activation results in a decrease in the tyrosine phosphorylation of Gab1 and a decreased association with the PI3K. SHP2 is shown to associate with and dephosphorylate Gab1, suggesting that EGFstimulated ERK might act through the regulation of SHP2.

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supporting

confidence: 66%

mentioning

confidence: 99%

ERK Negatively Regulates the Epidermal Growth Factor-mediated Interaction of Gab1 and the Phosphatidylinositol 3-Kinase

Liu

Cantley

2002

Journal of Biological Chemistry

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126

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“…The identity of Ser/Thr kinase(s) responsible for phosphorylating those Ser and Thr is currently unknown. The Ser/Thr phosphorylation of Gab1 by PKC or extracellular signal-regulated kinase has been shown to either positively or negatively regulate the tyrosine phosphorylation of Gab1 and its interaction with the other SH2 domain-containing proteins in response to growthfactor stimulation (Yu et al, 2001(Yu et al, , 2002Lehr et al, 2004). However, the effect of Ser/Thr phosphorylation identified in this study on tyrosine phosphorylation of Gab1 remains to be clarified.…”

Section: Discussionmentioning

confidence: 74%

Differential phosphorylation of the docking protein Gab1 by c-Src and the hepatocyte growth factor receptor regulates different aspects of cell functions

Lai

et al. 2009

Oncogene

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The docking protein Grb2-associated binder1 (Gab1) has a central role in the integration of the growth-factor signaling. In this study, we aimed to examine the significance of Src-mediated Gab1 phosphorylation in the hepatocyte growth factor (HGF) signaling. Using both mutagenesis and mass spectrometry approaches, Y242, Y259, Y317, Y373 and Y627 of Gab1 were identified to be phosphorylated by c-Src. It is interesting to note that the binding of the tyrosine phosphatase SHP2 to the Y627 antagonized the effect of c-Src on the phosphorylation of the other four tyrosine residues. Moreover, the tyrosine residues predominantly phosphorylated by c-Src were different from those predominantly phosphorylated by the HGF receptor. Gab1 overexpression potentiated both mitogenic and motogenic activities of HGF. However, a Gab1 mutant with substitutions of the Src phosphorylation sites (Y242, Y259, Y317 and Y373) failed to promote HGF-induced DNA synthesis, but retained its ability to facilitate HGF-induced chemotaxis. Taken together, our results not only suggest that the phosphorylation of Gab1 by c-Src is important for HGF-induced DNA synthesis, but also provide an example to illustrate how a docking protein (for example, Gab1) is differentially phosphorylated by c-Src and a receptor tyrosine kinase to emanate full spectrum of signals to the downstream.

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“…We also show that ERK might be involved in Akt activation. The ability of the RSK1 homologue MSK1 to phosphorylate and activate Akt was recently demonstrated (Hsu et al, 2001;Nomura et al, 2001;Yu et al, 2001). The mechanism by which RSK regulates Akt activation remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…If RSK associates with the KGFR, it seemed logical that RSK may actually be involved in Akt activation. Indeed, recent studies indicate that ERK may be involved in Akt activation under certain circumstances and the RSK homologue MSK was shown to phosphorylate and activate Akt (Hsu et al, 2001;Nomura et al, 2001;Yu et al, 2001). To test whether RSK1 is involved in Akt activation, we checked the Akt kinase activity in cells overexpressing wt or mutant RSK1 and stimulated by KGF.…”

Section: Rsk1 Is Required For Akt Activation By the Kgfrmentioning

confidence: 99%

Ribosomal S6 Kinase as a Mediator of Keratinocyte Growth Factor-induced Activation of Akt in Epithelial Cells

Pan

Devaux

Ray

2004

MBoC

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The keratinocyte growth factor receptor (KGFR) is a member of the fibroblast growth factor receptor (FGFR) superfamily. The proximal signaling molecules of FGFRs are much less characterized compared with other growth factor receptors. Using the yeast two-hybrid assay, we have identified ribosomal S6 kinase (RSK) to be a protein that associates with the cytoplasmic domain of the KGFR. The RSK family of kinases controls multiple cellular processes, and our studies for the first time show association between the KGFR and RSK. Using a lung-specific inducible transgenic system we have recently demonstrated protective effects of KGF on the lung epithelium and have demonstrated KGF-induced activation of the prosurvival Akt pathway both in vivo and in vitro. Here we show that a kinase inactive RSK mutant blocks KGF-induced Akt activation and KGF-mediated inhibition of caspase 3 activation in epithelial cells subjected to oxidative stress. It was recently shown that RSK2 recruits PDK1, the kinase responsible for both Akt and RSK activation. When viewed collectively, it appears that the association between the KGFR and RSK plays an important role in KGF-induced Akt activation and consequently in the protective effects of KGF on epithelial cells. INTRODUCTIONThe keratinocyte growth factor receptor (KGFR) is a member of the FGFR (fibroblast growth factor receptor) family. The KGFR is expressed only in epithelial cells and it plays critical roles in the proliferation, migration, and morphogenesis of epithelial cells (Ulich et al., 1994;Wilson et al., 1994;Post et al., 1996;Buckley et al., 1997). The KGFR also plays important roles in skin wound healing and lung epithelial cell survival during injury (Werner et al., 1994;Panos et al., 1995;Yi et al., 1996;Barazzone et al., 1999;Das and Olsen, 2001;Ray et al., 2003). The KGFR is activated by FGF-1, FGF-3, KGF/FGF-7, and FGF-10, whereas FGFR2 is mainly activated by FGF-2/bFGF (Bottaro et al., 1990;Miki et al., 1991Miki et al., , 1992Orr-Urtreger et al., 1993). In contrast to information on signaling by other growth factor receptors, the proximal signaling molecules of FGFRs are much less characterized.To characterize the KGFR-induced signaling pathways, we screened for proteins interacting with the KGFR cytoplasmic domain using the yeast two-hybrid assay. RSK1 is one of the proteins we identified and this interaction was confirmed in mammalian epithelial cells. The RSK (or p90RSK) family includes three members, RSK1-3, which show 75-80% similarity at the amino acid level (Frodin and Gammeltoft, 1999). RSK family members contain two heterologous kinase domains (Fisher and Blenis, 1996). The Nterminal kinase (NTK) domain belongs to the AGC group of kinases, which includes PKA, PKB/Akt, PKC, and PKG, and is the kinase domain that phosphorylates the substrates of RSKs. The C-terminal kinase (CTK) domain and the linker are involved in the activation of the RSK NTK domain (Frodin and Gammeltoft, 1999). At the carboxyl-terminus, there is an ERK-binding site conserved in all three RSK ...

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ERK Regulates the Hepatocyte Growth Factor-mediated Interaction of Gab1 and the Phosphatidylinositol 3-Kinase

Cited by 56 publications

References 37 publications

ERK Negatively Regulates the Epidermal Growth Factor-mediated Interaction of Gab1 and the Phosphatidylinositol 3-Kinase

ERK Negatively Regulates the Epidermal Growth Factor-mediated Interaction of Gab1 and the Phosphatidylinositol 3-Kinase

Differential phosphorylation of the docking protein Gab1 by c-Src and the hepatocyte growth factor receptor regulates different aspects of cell functions

Ribosomal S6 Kinase as a Mediator of Keratinocyte Growth Factor-induced Activation of Akt in Epithelial Cells

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