Role of Phosphatidylinositol Kinase in PDGF Receptor Signal Transduction

Coughlin, Shaun R.; Escobedo, Jaime A.; Williams, Lewis T.

doi:10.1126/science.2466336

Cited by 505 publications

(242 citation statements)

References 16 publications

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“…By contrast, many studies have implicated phospholipase C-b activation and enhanced phosphatidylinositol bisphosphate (PIP 2 ) hydrolysis in mitogenesis (Rozengurt, 1986). However, experiments utilizing mutant tyrosine kinase receptors provided evidence that PIP 2 hydrolysis may be neither necessary nor su cient for mitogenesis (Coughlin et al, 1989;Mohammadi et al, 1992). Consistent with those observations, a number of agonists acting on GPCRs, can e ectively induce PIP 2 -hydrolysis, but fail to stimulate growth when added alone to quiescent cells (Moolenaar, 1991).…”

Section: Mitogenic Signaling Through G Protein-coupled Receptorsmentioning

confidence: 99%

Cell growth control by G protein-coupled receptors: from signal transduction to signal integration

1998

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Section: Mitogenic Signaling Through G Protein-coupled Receptorsmentioning

confidence: 99%

Cell growth control by G protein-coupled receptors: from signal transduction to signal integration

1998

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“…This pathway can be activated by the q-adrenergic, LPA and dopamine D2 receptors (Luo et al, 1998), is PTX sensitive and mediated by the Gf3y subunits of the G,-coupled receptors. Gi-coupled GPCR regulation of adenylyl cyclase and PLCP has been shown to be neither necessary nor sufficient to account for mitogenesis (Coughlin et al, 1989;Mohammadi et al, 1992). Constitutive activation of components in GPCR signalling upstream of the MAPK pathway is sufficient for tumorigenesis (Mansour et al, 1994;.…”

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SH3 Binding Domains in the Dopamine D4 Receptor

Oldenhof

Vickery²,

Anafi³

et al. 1998

Biochemistry

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The dopamine D4 receptor is a G protein-coupled receptor (GPCR) that belongs to the dopamine D2-like receptor family. Functionally, the D2-like receptors are characterized by their ability to inhibit adenylyl cyclase. The dopamine D4 receptor as well as many other catecholaminergic receptors contain several putative SH3 binding domains. Most of these sites in the D4 receptor are located in a polymorphic repeat sequence and flanking sequences in the third intracellular loop. Here we demonstrate that this region of the D4 receptor can interact with a large variety of SH3 domains of different origin. The strongest interactions were seen with the SH2−SH3 adapter proteins Grb2 and Nck. The repeat sequence itself is not essential in this interaction. The data presented indicate that the different SH3 domains in the adapter proteins interact in a cooperative fashion with two distinct sites immediately upstream and downstream from the repeat sequence. Removal of all the putative SH3 binding domains in the third intracellular loop of the dopamine D4 receptor resulted in a receptor that could still bind spiperone and dopamine. Dopamine could not modulate the coupling of these mutant receptors to adenylyl cyclase and MAPK, although dopamine modulated receptor−G protein interaction appeared normal. The receptor deletion mutants show strong constitutive internalization that may account for the deficiency in functional activation of second messengers. The data indicates that the D4 receptor contains SH3 binding sites and that these sites fall within a region involved in the control of receptor internalization.

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“…More recently, a novel PI kinase that phosphorylates inositol at the D-3 position has been identified (57). This enzyme, known as PI 3-kinase (PI3K), has subsequently been found to associate with several tyrosine kinase oncogenes and proto-oncogenes (2,4,7,9,14). Furthermore, a strong correlation between the mitogenic response and associated PI3K activity in receptor-type tyrosine kinases has been reported (9,12,13,46).…”

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confidence: 99%

“…This enzyme, known as PI 3-kinase (PI3K), has subsequently been found to associate with several tyrosine kinase oncogenes and proto-oncogenes (2,4,7,9,14). Furthermore, a strong correlation between the mitogenic response and associated PI3K activity in receptor-type tyrosine kinases has been reported (9,12,13,46). Similarly, PI3K association with transforming or activated forms of pp60vsrC or pp60csrC and with polyomavirus middle-T antigen-c-Src complexes has suggested a possible correlation with cell transformation ability (4,7,10,24,56).…”

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The SH3 domain of p56lck is involved in binding to phosphatidylinositol 3'-kinase from T lymphocytes.

Vogel

Fujita

1993

Mol. Cell. Biol.

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Many of the Src-like tyrosine kinases are thought to participate in multiprotein complexes that modulate transmembrane signalling through tyrosine phosphorylation. We have used in vitro binding studies employing bacterially expressed glutathione S-transferase-p561k fusion proteins and cell extracts to map regions on p56kk that are involved in binding to phosphatidylinositol 3'-kinase (P13K). Deletions within the SH3 domain of pS6kk abolished binding of P13K activity from T-cell lysates, whereas deletion of the SH2 domain caused only a slight reduction in the level of P13K activity bound to p56kk sequences. The binding of P13K from T-cell extracts to p56kk was not blocked by antiphosphotyrosine antibodies, but p56-kkbound P13K activity was sensitive to phosphatase treatment. The SH3 domain of p56kk also bound the majority of P13K activity from uninfected chicken embryo fibroblasts. However, a drastically different binding specificity was observed with use of extracts of Rous sarcoma virus v-src-transformed cells, in which the majority of P13K activity bound to the SH2 domain of p56k in a phosphotyrosine-dependent manner. These results suggest that are two modes of PI3K binding to p56kk, and presumably to other Src-like tyrosine kinases. In one mode, PI3K from T cells or uninfected chicken embryo fibroblasts binds predominantly to the SH3 domain of p56kk. In the other mode, involving P13K from Rous sarcoma virus-transformed cells, binding is largely phosphotyrosine dependent and requires the SH2 domain of pS6kk.The Ick gene is a member of the src family of genes, which encode a series of eight closely related protein tyrosine kinases (for a review, see reference 23?. The product of the ick gene is a 56-kDa protein (p561 ) that is expressed predominantly in cells of the lymphoid lineage, primarily T lymphocytes and lymphoid tumor cell lines (28, 30, 37).Expression of p56" has also been observed in human carcinomas of the lung and colon (50).Members of the Src family of tyrosine kinases are characterized by an NH2-terminal unique region followed by three regions that contain different degrees of homology among all members of the family (23, 42). In p561ck, Src homology region 3 (SH3) extends from amino acids 56 to 114. The SH2 domain includes amino acids 115 to 221 and the SH1, or catalytic, domain comprises most of the remainder of the C-terminal half of the protein. Recent evidence indicates that the SH2 region of Src-like kinases functions as a protein association domain that is important in the formation of multienzyme complexes that regulate signal transduction through tyrosine phosphorylation (5, 27).Several proteins have been reported to form complexes with pS6lc in T lymphocytes. The NH2-terminal unique region of p56"kk has been shown to associate with the C-terminal region of two T-cell transmembrane glycoproteins, CD4 and CD8 (3,39,40,45,48). The accessory role of CD4 and CD8 in T-cell signalling has led to the suggestion that p56"'" may participate in antigen-stimulated signal transduction events (18,36)....

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Role of Phosphatidylinositol Kinase in PDGF Receptor Signal Transduction

Cited by 505 publications

References 16 publications

Cell growth control by G protein-coupled receptors: from signal transduction to signal integration

Cell growth control by G protein-coupled receptors: from signal transduction to signal integration

SH3 Binding Domains in the Dopamine D4 Receptor

The SH3 domain of p56lck is involved in binding to phosphatidylinositol 3'-kinase from T lymphocytes.

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