GTPase-activating protein and phosphatidylinositol 3-kinase bind to distinct regions of the platelet-derived growth factor receptor beta subunit.

Kazlauskas, Andrius; Kashishian, Adam; Cooper, Jonathan A.; Valius, Mindaugas

doi:10.1128/mcb.12.6.2534

Cited by 229 publications

(148 citation statements)

References 56 publications

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“…This veri®es that PI3K and its downstream targets, rather than an unidenti®ed e ector, convey the mitogenic e ects of RasC40. PI3K exhibits a well-established role in cell proliferation (Fantl et al, 1992;Kazlauskas et al, 1992;Roche et al, 1994;Jhun et al, 1994;Cheatham et al, 1994). Acute or inducible expression of p110-CAAX stimulates growth factor-independent DNA synthesis in other cells (Klippel et al, 1998;Frevert and Kahn, 1997).…”

Section: Discussionmentioning

confidence: 99%

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Cass

Meinkoth

2000

Oncogene

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Hormones are specialized mitogens that stimulate proliferation in their di erentiated target cells. Thyrotropin (TSH), the physiologic regulator of thyroid cells, stimulates cAMP-mediated proliferation and thyroidspeci®c gene expression. The mitogenic e ects of TSH require Ras, therefore Ras activation should be compatible with the maintenance of thyroid di erentiation. However, expression of activated Ras extinguishes the di erentiated phenotype of thyroid cells. One explanation for this apparent paradox is the selective utilization of Ras e ector pathways. We tested the hypothesis that Ras signaling through PI3K mediates the mitogenic e ects of TSH in cells which retain their di erentiated character. Expression of a Ras e ector mutant (RasV12S35) that signals preferentially through Raf-1, although su cient to confer TSH-independent proliferation, abolished hormone-regulated expression of thyroglobulin and the sodium/iodide symporter. In contrast, expression of a Ras mutant (RasV12C40) that binds selectively to PI3K conferred TSH-independent proliferation without marked e ects on thyroid-speci®c gene expression. Unlike the inhibitory e ects of TSH on the proliferation of RasV12S35-expressing cells, TSH enhanced RasV12C40-stimulated proliferation by further increasing the activity of p70s6k, an important mediator of the mitogenic e ects of TSH and RasV12C40. These results demonstrate that channeling Ras-dependent signals to PI3K confers TSH with the ability to stimulate proliferation in di erentiated cells. Oncogene (2000) 19, 924 ± 932.

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Section: Discussionmentioning

confidence: 99%

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Cass

Meinkoth

2000

Oncogene

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“…2), it is evident that one or more of these tyrosines are involved in PDGFinduced disruption of GJC and Cx43 phosphorylation. To understand the roles of each tyrosine and its corresponding signaling pathway, T51B cells were retrovirally infected with a panel of mutant PDGFR␤ constructs in which individual tyrosines were mutated to prevent the recruitment of a specific signaling molecule (43). These single-site mutants include 740/ 751 Ϫ , 771 Ϫ , 1009 Ϫ , and 1021 Ϫ , which lack the binding sites for PI3K, GAP, SHP-2, and PLC␥1, respectively.…”

Section: Resultsmentioning

confidence: 99%

Disruption of Gap Junctional Communication by the Platelet-derived Growth Factor Is Mediated via Multiple Signaling Pathways

Hossain

Jagdale

et al. 1999

Journal of Biological Chemistry

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The platelet-derived growth factor (PDGF) mediates its cellular functions via activation of its receptor tyrosine kinase followed by the recruitment and activation of several signaling molecules. These signaling molecules then initiate specific signaling cascades, finally resulting in distinct physiological effects. To delineate the PDGF signaling pathway responsible for the disruption of gap junctional communication (GJC), wild-type PDGF receptor ␤ (PDGFR␤) and a series of PDGFR␤ mutants were expressed in T51B rat liver epithelial cells. In cells expressing wild-type PDGFR␤, PDGF induced disruption of GJC and phosphorylation of a gap junctional protein, connexin-43 (Cx43), which required activation of mitogen-activated protein kinase, although involvement of additional factors was also evident. In the F5 mutant lacking binding sites for phosphatidylinositol 3-kinase, GTPase-activating protein, SHP-2, and phospholipase C␥1 (PLC␥1), PDGF induced mitogen-activated protein kinase, but failed to affect GJC or Cx43, indicating involvement of additional signals presumably initiated by one or more of the mutated binding sites. Examination of the single-site mutants revealed that PDGF effects were not mediated via a single signaling component. This was confirmed by the "add-back" mutants, which showed that restoration of either SHP-2 or PLC␥1 binding was sufficient to propagate the GJC inhibitory actions of PDGF. Further analysis showed that activation of PLC␥1 is involved in Cx43 phosphorylation, which surprisingly failed to correlate with GJC blockade. The results of our study demonstrate that PDGF-induced disruption of GJC can be mediated by multiple signaling pathways and requires participation of multiple components.

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“…While PI3K, PLC␥, and Src have been shown to be required for initiation of DNA synthesis by the ␤PDGFR, the ␣PDGFR does not seem to require either PI3K or PLC␥ for mitogenic signaling (15,17,30,59,60,68,69). The involvement of Src in ␣PDGFR signal relay has not yet been investigated.…”

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confidence: 99%

Phosphorylation of Tyrosine 720 in the Platelet-Derived Growth Factor α Receptor Is Required for Binding of Grb2 and SHP-2 but Not for Activation of Ras or Cell Proliferation

Bazenet

Gelderloos

Kazlauskas

1996

Molecular and Cellular Biology

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Following binding of platelet-derived growth factor (PDGF), the PDGF ␣ receptor (␣PDGFR) becomes tyrosine phosphorylated and associates with a number of signal transduction molecules, including phospholipase C␥-1 (PLC␥-1), phosphatidylinositol 3-kinase (PI3K), the phosphotyrosine phosphatase SHP-2, Grb2, and Src. Here, we present data identifying a novel phosphorylation site in the kinase insert domain of the ␣PDGFR at tyrosine (Y) 720. We replaced this residue with phenylalanine and expressed the mutated receptor (F720) in Patch fibroblasts that do not express the ␣PDGFR. Characterization of the F720 mutant indicated that binding of two proteins, SHP-2 and Grb2, was severely impaired, whereas PLC␥-1 and PI3K associated to wild-type levels. In addition, mutating Y720 to phenylalanine dramatically reduced PDGF-dependent tyrosine phosphorylation of SHP-2. Since Y720 was required for recruitment of two proteins, we investigated the mechanism by which these two proteins associated with the ␣PDGFR. SHP-2 bound the ␣PDGFR directly, whereas Grb2 associated indirectly, most probably via SHP-2, as Grb2 and SHP-2 coimmunoprecipitated when SHP-2 was tyrosine phosphorylated. We also compared the ability of the wild-type and F720 ␣PDGFRs to mediate a number of downstream events. Preventing the ␣PDGFR from recruiting SHP-2 and Grb2 did not compromise PDGF-AA-induced activation of Ras, initiation of DNA synthesis, or growth of cells in soft agar. We conclude that phosphorylation of the ␣PDGFR at Y720 is required for association of SHP-2 and Grb2 and tyrosine phosphorylation of SHP-2; however, these events are not required for the ␣PDGFR to activate Ras or initiate a proliferative response. In addition, these findings reveal that while SHP-2 binds to both of the receptors, it binds in different locations: to the carboxy terminus of the ␤PDGFR but to the kinase insert of the ␣PDGFR.

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GTPase-activating protein and phosphatidylinositol 3-kinase bind to distinct regions of the platelet-derived growth factor receptor beta subunit.

Cited by 229 publications

References 56 publications

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Disruption of Gap Junctional Communication by the Platelet-derived Growth Factor Is Mediated via Multiple Signaling Pathways

Phosphorylation of Tyrosine 720 in the Platelet-Derived Growth Factor α Receptor Is Required for Binding of Grb2 and SHP-2 but Not for Activation of Ras or Cell Proliferation

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