Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor.

Nishimura, Riko; Li, W; Kashishian, Adam; Mondino, Anna; Zhou, Min; Cooper, Jonathan A.; Schlessinger, Joseph

doi:10.1128/mcb.13.11.6889

Cited by 172 publications

(129 citation statements)

References 46 publications

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“…The two other sites, Tyr579 and Tyr581 are located in the juxtamembrane domain of the b-receptor and have been shown to serve as binding sites for Src family kinases. It has been shown previously that signal transduction molecules may compete for binding to the same site on the PDGF b-receptor (Nishimura et al, 1993). In this context, it is noteworthy that v-Src has been described to associate with Stat3 in v-Src transformed cells and that Src is able to phosphorylate and activate Stat3 (Cao et al, 1996;Yu et al, 1995 (Figure 7 and data not shown), whereas no appreciable decrease in phosphorylation of Stat5 was seen in cells with Y771F or Y778F mutant receptors.…”

Section: Discussionsupporting

confidence: 53%

“…Two autophosphorylation sites in the juxtamembrane domain (Tyr579 and Tyr581) mediate binding of Src family kinases (Mori et al, 1993). Autophosphorylation sites in the kinase insert bind Grb2 (Tyr716; Arvidsson et al, 1994), the regulatory subunit (p85) of phosphatidylinositol 3-kinase (Tyr740 and Tyr751; Fantl et al, 1992;Kashishian et al, 1992), Nck (Tyr751; Nishimura et al, 1993), and the GTPase-activating protein of Ras (Tyr771; Fantl et al, 1992;Kashishian et al, 1992). Two autophosphorylation sites in the C-terminal tail mediate binding of phospholipase C-g (Tyr1009 and Tyr1021; Kashishian and Cooper, 1993;RoÈ nnstrand et al, 1992;Valius et al, 1993), Tyr1009 in addition binds the tyrosine phosphatase SHP2 .…”

Section: Introductionmentioning

confidence: 99%

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Activation of Stat5 by platelet-derived growth factor (PDGF) is dependent on phosphorylation sites in PDGF β-receptor juxtamembrane and kinase insert domains

et al. 1998

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Signal transducers and activators of transcription (Stats) are known to transduce signals from the cell surface to the nucleus in cytokine receptor signaling. We examined the capacity of platelet-derived growth factor (PDGF) receptor to interact with and activate Stat molecules. Activation of the PDGF b-receptor led to tyrosine phosphorylation of Stat1, Stat3 and Stat5, which was accompanied by speci®c DNA-binding activities. These events were only weakly stimulated by the activated PDGF a-receptor. In cells expressing PDGF b-receptors mutated at Tyr579, Tyr581 or Tyr775, tyrosine phosphorylation as well as DNA-binding activity of Stat5 was reduced. Immobilized peptides containing phosphorylated Tyr579, Tyr581 or Tyr775 bound Stat5, suggesting direct binding of Stat5 to these tyrosine residues of the PDGF b-receptor. Members of the Janus kinase family were also shown to interact with the PDGF b-receptor, and to a lesser extent with the areceptor, but their importance for PDGF-induced Stat activation remains to be determined.

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Section: Discussionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Activation of Stat5 by platelet-derived growth factor (PDGF) is dependent on phosphorylation sites in PDGF β-receptor juxtamembrane and kinase insert domains

et al. 1998

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“…Following growth factor stimulation, Nck has been found in complexes with a number of phosphotyrosine proteins including the receptor tyrosine kinases Nishimura et al, 1993). However, except for the receptors, identity of the other Nck-associated phosphotyrosine proteins remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Induced direct binding of the adapter protein Nck to the GTPase-activating protein-associated protein p62 by epidermal growth factor

Tang

Feng

1997

Oncogene

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The SH3-SH3-SH3-SH2 adapter protein Nck links receptor tyrosine kinases, such as EGF and PDGF receptors, to downstream signaling pathways, among which p21 cdc42/rac -activated kinase cascade, Sos-activated Ras signaling and the human Wiskott-Aldrich Syndrome protein (WASp)-mediated actin cytoskeleton changes, have been implicated. In EGF stimulated cells, Nck coimmunoprecipitates with a number of phosphotyrosine proteins including the EGF receptor (Li et al., 1992 Mol. Cell. Biol. 12: 5824 ± 2833). To identify the phosphotyrosine protein(s) that directly interacts with Nck and to distinguish it from indirectly associated proteins, preexisting phosphoytrosine protein complexes in the cell lysate were dissociated by heat and SDS prior to the test for binding to Nck. We found that Nck does not directly bind to EGF receptor, instead it binds via its SH2 domain to a 62 kDa phosphotyrosine protein. We present evidence demonstrating that the Nck-bound p62 is related to the previously identi®ed GTPase-activating protein (GAP)-associated phosphotyrosine protein p62.(1) The Nck-bound and the GAP-bound p62 proteins comigrate with each other in SDS ± PAGE. (2) SH2 domains from Nck and GAP compete for binding to p62 in vitro. (3) Puri®ed GST-Nck-SH2 binds directly to the GAP-associated p62. Under these conditions, SH2 domains from PLCg, PI-3 kinase, SHC, and Grb2 did not bind p62. (4) Tryptic phosphopeptide maps of the Nck-and the GAP-associated p62 proteins are identical. However, Nck and GAP do not co-immunoprecipitate with each other and apparently bind to di erent pools of p62. This study suggests that the GAP-associated p62 acts as an SH2 domain docking protein and mediates the interaction between Nck and EGF receptor in response to EGF stimulation.

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“…It has been well established that Nck-1 can associate with several components of receptor tyrosine kinase-signaling pathways including EGF receptor (Li et al, 1992;Park and Rhee, 1992), PDGF receptor (Li et al, 1992;Nishimura et al, 1993), and IRS-1 (Lee et al, 1993) upon ligand activation. To test whether Nck-2 could recognize EGF receptors, we analyzed the ability of GST-Nck-2 (Figure 4, lane 1) to associate with EGF receptors from human A431 cells that were either serum starved or stimulated with EGF ( Figure 5).…”

Section: Association Of Nck-2 With Egf Receptor and Its Regulation Bymentioning

confidence: 99%

Nck-2, a Novel Src Homology2/3-containing Adaptor Protein That Interacts with the LIM-only Protein PINCH and Components of Growth Factor Receptor Kinase-signaling Pathways

1998

MBoC

167

166

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Many of the protein-protein interactions that are essential for eukaryotic intracellular signal transduction are mediated by protein binding modules including SH2, SH3, and LIM domains. Nck is a SH3-and SH2-containing adaptor protein implicated in coordinating various signaling pathways, including those of growth factor receptors and cell adhesion receptors. We report here the identification, cloning, and characterization of a widely expressed, Nck-related adaptor protein termed Nck-2. Nck-2 comprises primarily three Nterminal SH3 domains and one C-terminal SH2 domain. We show that Nck-2 interacts with PINCH, a LIM-only protein implicated in integrin-linked kinase signaling. The PINCHNck-2 interaction is mediated by the fourth LIM domain of PINCH and the third SH3 domain of Nck-2. Furthermore, we show that Nck-2 is capable of recognizing several key components of growth factor receptor kinase-signaling pathways including EGF receptors, PDGF receptor-␤, and IRS-1. The association of Nck-2 with EGF receptors was regulated by EGF stimulation and involved largely the SH2 domain of Nck-2, although the SH3 domains of Nck-2 also contributed to the complex formation. The association of Nck-2 with PDGF receptor-␤ was dependent on PDGF activation and was mediated solely by the SH2 domain of Nck-2. Additionally, we have detected a stable association between Nck-2 and IRS-1 that was mediated primarily via the second and third SH3 domain of Nck-2. Thus, Nck-2 associates with PINCH and components of different growth factor receptor-signaling pathways via distinct mechanisms. Finally, we provide evidence indicating that a fraction of the Nck-2 and/or Nck-1 proteins are associated with the cytoskeleton. These results identify a novel Nck-related SH2-and SH3-domain-containing protein and suggest that it may function as an adaptor protein connecting the growth factor receptor-signaling pathways with the integrin-signaling pathways.

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Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor.

Cited by 172 publications

References 46 publications

Activation of Stat5 by platelet-derived growth factor (PDGF) is dependent on phosphorylation sites in PDGF β-receptor juxtamembrane and kinase insert domains

Activation of Stat5 by platelet-derived growth factor (PDGF) is dependent on phosphorylation sites in PDGF β-receptor juxtamembrane and kinase insert domains

Induced direct binding of the adapter protein Nck to the GTPase-activating protein-associated protein p62 by epidermal growth factor

Nck-2, a Novel Src Homology2/3-containing Adaptor Protein That Interacts with the LIM-only Protein PINCH and Components of Growth Factor Receptor Kinase-signaling Pathways

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