The Shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (Y239/240) that mediate protein–protein interactions

Geer, Peter van der; Wiley, Sandra E.; Gish, Gerald; Pawson, Tony

doi:10.1016/s0960-9822(96)00748-8

Cited by 212 publications

(207 citation statements)

References 37 publications

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“…Shc has previously been shown to be phosphorylated following activation of a number of growth factor receptors, at Tyr317, Tyr239 and Tyr240 (Salcini et al, 1994;van der Geer et al, 1996). Phosphorylated Tyr317 constitutes a consensus binding site for Grb2 (Salcini et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

et al. 1999

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In this report we show that Tyr568 and Tyr570 are phosphorylated in vivo in the Kit/stem cell factor receptor (Kit/SCFR) following ligand-stimulation. By mutation of Tyr568 and Tyr570 to phenylalanine residues and expression of the mutated receptors in porcine aortic endothelial (PAE) cells, we could demonstrate a loss of activation of members of the Src family of tyrosine kinases when Tyr568 was mutated, while mutation of Tyr570 only led to a minor decrease in activation of Src family members. Mutation of both tyrosine residues led to a complete loss of Src family kinase activation. Phosphorylation of the adapter protein Shc by growth factor receptors provides association sites for Grb2-Sos, thereby activating the Ras/MAP kinase pathway. A much lowered degree of Shc phosphorylation, Ras and Erk2 activation and c-fos induction was seen in the Y568F mutant, while in the Y570F mutant these responses were less a ected. In contrast, the mitogenic response was only slightly reduced. In a mutant receptor with both Tyr568 and Tyr570 mutated to phenylalanine residues, no phosphorylation of Shc and no activation of Ras and Erk2 was seen in response to stem cell factor stimulation, very weak induction of c-fos was seen and the mitogenic response was severely depressed. These data show that Ras/MAP kinase activation and c-fos induction by Kit/SCFR are mediated by members of the Src family kinases. However, the mitogenic response is only to a minor extent dependent on Src kinase activity.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

et al. 1999

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“…Both sites are GRB2 binding sites (Gotoh et al, 1996(Gotoh et al, , 1997van der Geer et al, 1996;Harmer and DeFranco, 1997). To determine whether one of these sites is preferentially phosphorylated after FLT4L activation, we mutated each tyrosine to phenylalanine and expressed the SHC mutants in FF4L RAT2 cells.…”

Section: Y313 and Y239/y240 Tyrosines Of Shc Are Targeted By Flt4lmentioning

confidence: 99%

“…More recent data have shown that a tandem of tyrosines (Y239/Y240) present in the CH1 region is phosphorylated following EGF or IL3 stimulation and represents an additional high a nity GRB2 binding site. Y239/Y240 and Y313 may mediate di erent signal to the nucleus (Gotoh et al, 1996(Gotoh et al, , 1997van der Geer et al, 1996;Harmer and DeFranco, 1997). Both Y239 and Y240 can be either equally phosphorylated or with di erent kinetics or at di erent levels, depending on the stimulus (Harmer and DeFranco, 1997;Gotoh et al, 1997) The VEGFR3/ FLT4 receptor belongs to the family of VEGF receptors.…”

Section: Introductionmentioning

confidence: 99%

Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF Receptor 3 signaling

et al. 1999

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The VEGFR3/FLT4 receptor, which is involved in vasculogenesis and angiogenesis, binds and phosphorylates SHC proteins on tyrosine residues. SHC contains two phosphotyrosine interaction domains: a PTB (Phosphotyrosine Binding) and a SH2 (Src Homology 2) domain. Previous studies have shown that SHC proteins are phosphorylated on Y239/Y240 and Y313 (Y317 in humans) by tyrosine kinases such as the EGF and IL3 receptors. We have investigated which of the SHC tyrosine residues are targeted by the VEGFR3/ FLT4 kinase and the role of the SHC PTB and SH2 domains in this process. Our results show that Y239/ Y240 and Y313 are simultaneously phosphorylated by the kinase, creating GRB2 binding sites. Mutation of SHC PTB, but not SH2, domain interferes with the SHC phosphorylation by VEGFR3/FLT4. Soft agar assay experiments revealed that the VEGFR3/FLT4 transforming capacity is increased by the mutation of Y239/Y240 to phenylalanines in SHC, suggesting that these two residues mediate an inhibitory signal for cell growth. Mutation of the two phosphorylation sites increases this e ect, suggesting that they have a synergistic role.

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“…Two additional sites of Shc tyrosine phosphorylation have recently been mapped to tyrosine residues 239 and 240 (Y239/ 240) (Gotoh et al, 1996;Harmer and DeFranco, 1997;van der Geer et al, 1996). Tyrosine 239 is present within a Grb2 SH2 domain-binding motif, and has been demonstrated to mediate association with Grb2 in vivo (Gotoh et al, 1997;Harmer and DeFranco, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Tyrosine 239 is present within a Grb2 SH2 domain-binding motif, and has been demonstrated to mediate association with Grb2 in vivo (Gotoh et al, 1997;Harmer and DeFranco, 1997). The Y239/240 phosphorylation sites may also couple Shc to additional downstream SH2 domain-containing proteins, since phosphopeptides corresponding to Y239/240 have been demonstrated to bind to several unidenti®ed proteins and to the newly identi®ed adaptor protein Gads (van der Geer et al, 1996;Liu and McGlade, 1998). A novel role for Shc has been suggested in which phosphorylation of Y239/Y240 leads to c-myc induction and suppression of apoptosis in Ba/F3 cells, in a Ras-independent manner (Gotoh et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells

1999

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The Shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (Y239/240) that mediate protein–protein interactions

Cited by 212 publications

References 37 publications

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF Receptor 3 signaling

Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells

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