Tyrosine phosphorylation of G protein alpha subunits by pp60c-src.

Hausdorff, William P.; Pitcher, Julie A.; Luttrell, Deirdre K.; Linder, Maurine E.; Kurose, Hitoshi; Parsons, Sarah J.; Caron, Marc G.; Lefkowitz, Robert J.

doi:10.1073/pnas.89.13.5720

Cited by 107 publications

(78 citation statements)

References 52 publications

(41 reference statements)

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“…It has been proposed that the tyrosine-phosphorylation of Ga q/11 plays a role in their interactions with their receptors (Umemori et al, 1997). In this context, it is noteworthy that Ga s as well as Ga i can also be phosphorylated in vitro by Src (Hausdor et al, 1992). In these studies, it has been observed that the immunoprecipitated Src preferentially phosphorylates the puri®ed Ga s and Ga i in an immunecomplex kinase assay.…”

Section: G Protein Interactions With Other Signaling Pathwaysmentioning

confidence: 99%

Regulation of cell proliferation by G proteins

Dhanasekaran

Tsim²,

Dermott³

et al. 1998

Oncogene

136

107

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G Proteins provide signal transduction mechanisms to seven transmembrane receptors. Recent studies have indicated that the a-subunits as well as the bg-subunits of these proteins regulate several critical signaling pathways involved in cell proliferation, di erentiation and apoptosis. Of the 17 a-subunits that have been cloned, at least ten of them have been shown to couple mitogenic signaling in ®broblast cells. Activating mutations in Ga s , Ga i2 , and Ga 12 have been correlated with di erent types of tumors. In addition, the ability of the bg-subunits to activate mitogenic pathways in di erent cell-types has been de®ned. The present review brie¯y summarizes the diverse and novel signaling pathways regulated by the a-as well as the bg-subunits of G proteins in regulating cell proliferation.

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Section: G Protein Interactions With Other Signaling Pathwaysmentioning

confidence: 99%

Regulation of cell proliferation by G proteins

Dhanasekaran

Tsim²,

Dermott³

et al. 1998

Oncogene

136

107

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“…Interestingly, activation of G protein-coupled receptors is also associated with increased tyrosine phosphorylation (18,40), and Gas subunits are substrates for tyrosine phosphorylation by pp6Oc-s? (19).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of thyrotropin-stimulated DNA synthesis by microinjection of inhibitors of cellular Ras and cyclic AMP-dependent protein kinase.

Kupperman¹,

Wen²,

Meinkoth³

1993

Mol. Cell. Biol.

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Microinjection of a dominant interfering mutant of Ras (N17 Ras) caused a significant reduction in thyrotropin (thyroid-stimulating hormone [TSHJ)-stimulated DNA synthesis in rat thyroid cells. A similar reduction was observed following injection of the heat-stable protein kinase inhibitor of the cyclic AMPdependent protein kinase. Coinjection of both inhibitors almost completely abolished TSH-induced DNA synthesis. In contrast to TSH, overexpression of cellular Ras protein did not stimulate the expression of a cyclic AMP response element-regulated reporter gene. Similarly, injection of N17 Ras had no effect on TSHstimulated reporter gene expression. Moreover, overexpression of cellular Ras protein stimulated similar levels of DNA synthesis in the presence or absence of the heat-stable protein kinase inhibitor. Together, these results suggest that in Wistar rat thyroid cells, a full mitogenic response to TSH requires both Ras and cyclic APK-dependent protein kinase.The ras gene family is one member of a nucleotide-binding superfamily which participates in a diverse range of cellular activities, including growth, differentiation, and protein trafficking. Experimental evidence has shown that Ras is involved in growth factor-stimulated proliferation in many cell types. Sequencing and crystallographic data revealed that Ras shares structural homology with heterotrimeric G proteins. Ras and heterotrimeric G proteins are also functionally related; both contain intrinsic GTPase activity and alternate between active and inactive states, depending on whether GTP or GDP is bound. Oncogenic forms of the Ras protein are generated by mutations which reduce the protein's normal GTPase activity or eliminate the enhancement of its GTPase activity by GTPase-activating protein (GAP) (43). One result of these mutations is a constitutively active signaling molecule. Oncogenic Ras stimulates proliferation in fibroblasts and differentiation in PC12 cells (4,14,35). Conversely, disruption of Ras function with anti-Ras antibodies or a dominant interfering mutant of Ras (N17 Ras) blocks mitogenic responses to platelet-derived growth factor, epidermal growth factor, insulin, and serum in fibroblasts (6, 7, 31) and neuronal differentiation induced by nerve growth factor in PC12 cells (39).One common feature of Ras-regulated signaling has been its role in downstream events initiated by receptor tyrosine kinases. Although many growth factors stimulate proliferation through receptors containing (or associated with) tyrosine kinase activity, there are a large number of mitogenic peptides and hormones which stimulate proliferation through G protein-coupled receptors (10,17,25,28) (30). TSH treatment activates adenylyl cyclase activity, resulting in increased levels of intracellular cyclic AMP (cAMP) and activation of the cAMP-dependent protein kinase (cAPK). This pathway is thought to be the primary signaling pathway induced by TSH in most thyroid cells. Thyroid follicular cells also respond to alterations in Ras activity. Several investigator...

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“…In addition, it has been reported that a subunits of heterotrimeric class G proteins can be phosphorylated on tyrosine residues by the insulin receptor (31) and c-Src (21 (3,41). Thus, it is unlikely that HaRas is the G protein implicated here, which functions upstream from PKC.…”

Section: Discussionmentioning

confidence: 99%

Evidence that v-Src-induced phospholipase D activity is mediated by a G protein.

Jiang¹,

Alexandropoulos²,

Song³

et al. 1994

Mol. Cell. Biol.

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v-Src-induced increases in diglyceride are derived from phosphatidylcholine via a type D phospholipase (PLD) and a phosphatidic acid phosphatase. v-Src-induced PLD activity, as measured by PLD-catalyzed transphosphatidylation of phosphatidylcholine to phosphatidylethanol, is inhibited by GDPIS, which inhibits G-protein-mediated intracellular signals. Similarly, v-Src-induced increases in diglyceride are also blocked by GDPISS. In contrast to the PLD activity induced by v-Src, PLD activity induced by the protein kinase C agonist, 12-0-tetradecanoylphorbol-13-acetate (TPA), was insensitive to GDPIIS. Consistent with the involvement of a G protein in the activation of PLD activity by v-Src, GTP-yS, a nonhydrolyzable analog of GTP that potentiates G-protein-mediated signals, strongly enhanced PLD activity in v-Src-transformed cells relative to that in parental BALB/c 3T3 cells. v-Src was dependent upon the presence of ATP but was unaffected by either cholera or pertussis toxin. These data suggest that v-Src induces PLD activity through a phosphorylation event and is mediated by a cholera and pertussis toxin-insensitive G protein.Cellular transformation involves the disruption of intracellular signaling mechanisms (see reference 12 for a review). Protein-tyrosine kinase activity is frequently an early event in the transduction of intracellular signals and has been extensively implicated in transformation tumorigenesis (12). The oncogenic protein-tyrosine kinase, v-Src, transforms cells because of a constitutively active kinase (22). As a result of this constitutively active kinase activity, v-Src activates multiple intracellular signaling mechanisms that lead to the induction of gene expression (17,41,43). Protein kinase C (PKC) is a serine/threonine-specific protein kinase that has been implicated in v-Src-induced intracellular signaling (20,38,43,45,51,53), although not all intracellular signals activated by v-Src involve PKC (41, 43). PKC is activated by the phospholipid metabolite diglyceride (DG) (37). DG is frequently generated by the phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (see references 16 and 17 for a review); however, v-Src-induced increases in DG are derived from phosphatidylcholine (PC) via the action of a type D phospholipase (PLD) and a phosphatidic acid phosphatase (50). The activation of PLD by v-Src was found to be independent of PKC (48). Thus, it is likely that the DG produced by the PLD-phosphatidic acid phosphatase mechanism is responsible for the activation of PKC by v-Src. (18,31,33,34), epidermal growth factor (26, 27, 55), and colony-stimulating factor 1 (24, 25) receptors. G proteins have also been implicated in mediating the effects of c-Src on the ,-adrenergic response (11,36). We previously demonstrated that the activation of PKC-dependent gene expression and phosphorylation of the PKC substrate MARCKS by the related protein-tyrosine kinase v-Fps is dependent on a G protein (1). Since PKC is presumably the target of the PLDgenerated DG, these data su...

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Tyrosine phosphorylation of G protein alpha subunits by pp60c-src.

Cited by 107 publications

References 52 publications

Regulation of cell proliferation by G proteins

Regulation of cell proliferation by G proteins

Inhibition of thyrotropin-stimulated DNA synthesis by microinjection of inhibitors of cellular Ras and cyclic AMP-dependent protein kinase.

Evidence that v-Src-induced phospholipase D activity is mediated by a G protein.

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