An 11-Amino Acid Sequence from c-met Initiates Epithelial Chemotaxis via Phosphatidylinositol 3-Kinase and Phospholipase C

Derman, Melanie P.; Chen, Jean Y.; Spokes, Katherine; Songyang, Zhou; Cantley, Lloyd G.

doi:10.1074/jbc.271.8.4251

Cited by 58 publications

(38 citation statements)

References 21 publications

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“…Although it is generally believed that SH2 domains of p85 preferentially bind to receptor tyrosine kinases through this motif, other binding sites for p85 of PI3K have been described. For instance, p85 binding to the hepatocyte growth factor receptor family, including c-Met, c-Ron, and c-Sea is mediated by the YVHV sequence (31,32). Similarly, it has been demonstrated that amino acids YVNA on VEGFR-1 is a binding site for p85 (33).…”

Section: Vegfr-2 Activates Pi3kmentioning

confidence: 99%

Identification of Tyrosine Residues in Vascular Endothelial Growth Factor Receptor-2/FLK-1 Involved in Activation of Phosphatidylinositol 3-Kinase and Cell Proliferation

Dayanir¹,

Meyer

Lashkari

et al. 2001

Journal of Biological Chemistry

154

137

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Activation of vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in vasculogenesis and angiogenesis. However, the mechanism by which VEGFR-2 activation elicits these cellular events is not fully understood. We recently constructed a chimeric receptor containing the extracellular domain of human CSF-1R/c-fms, fused with the entire transmembrane and cytoplasmic domains of murine VEGFR-2 (Rahimi, N., Dayanir, V., and Lashkari, K. (2000) J. Biol. Chem. 275, 16986 -16992). In this study we used VEGFR-2 chimera (herein named CKR) to elucidate the signal transduction relay of VEGFR-2 in porcine aortic endothelial (PAE) cells. Mutation of tyrosines 799 and 1173 individually on CKR resulted in partial loss of CKR's ability to stimulate cell growth. Double mutation of these sites caused total loss of CKR's ability to stimulate cell growth. Interestingly, mutation of these sites had no effect on the ability of CKR to stimulate cell migration. Further analysis revealed that tyrosines 799 and 1173 are docking sites for p85 of phosphatidylinositol 3-kinase (PI3K). Pretreatment of cells with wortmannin, an inhibitor of PI3K, and rapamycin, a potent inhibitor of S6 kinase, abrogated CKR-mediated cell growth. However, expression of a dominant negative form of ras (N 17 ras) and inhibition of the mitogen-activated protein kinase (MAPK) pathway by PD98059 did not attenuate CKR-stimulated cell growth. Altogether, these results demonstrate that activation of VEGFR-2 results in activation of PI3K and that activation of PI3K/S6kinase pathway, but not Ras/MAPK, is responsible for VEGFR-2-mediated cell growth.

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Section: Vegfr-2 Activates Pi3kmentioning

confidence: 99%

Identification of Tyrosine Residues in Vascular Endothelial Growth Factor Receptor-2/FLK-1 Involved in Activation of Phosphatidylinositol 3-Kinase and Cell Proliferation

Dayanir¹,

Meyer

Lashkari

et al. 2001

Journal of Biological Chemistry

154

137

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“…3 H]inositol polyphosphates were analyzed by anion-exchange HPLC, using a Partisphere SAX column (Whatman), as described previously (2). All experiments were performed in triplicate.…”

Section: Ptdins-345-p 3 Directmentioning

confidence: 99%

“…Activation of the receptor-associated phosphoinositide 3-kinase (PI3K) 1 has been shown to cause mitogenesis and enhanced cell motility, although the exact mechanism by which PI3K mediates cell signaling during these events has been difficult to elucidate (1)(2)(3). The lipid products of PI3K have now been found to activate certain calcium-independent protein kinases C and to bind to a subset of Src homology 2 (SH2) domains (4,5).…”

mentioning

confidence: 99%

Phosphoinositide 3-Kinase Regulates Phospholipase Cγ-mediated Calcium Signaling

Rameh¹,

Rhee²,

Spokes³

et al. 1998

Journal of Biological Chemistry

Self Cite

213

185

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It has been demonstrated that the lipid products of the phosphoinositide 3-kinase (PI3K) can associate with the Src homology 2 (SH2) domains of specific signaling molecules and modify their actions. In the current experiments, phosphatidylinositol 3,4,5-trisphosphate (PtdIns-3,4,5-P 3 ) was found to bind to the C-terminal SH2 domain of phospholipase C␥ (PLC␥) with an apparent K d of 2.4 M and to displace the C-terminal SH2 domain from the activated platelet-derived growth factor receptor (PDGFR). To investigate the in vivo relevance of this observation, intracellular inositol trisphosphate (IP 3 ) generation and calcium release were examined in HepG2 cells expressing a series of PDGFR mutants that activate PLC␥ with or without receptor association with PI3K. Coactivation of PLC␥ and PI3K resulted in an ϳ40% increase in both intracellular IP 3 generation and intracellular calcium release as compared with selective activation of PLC␥. Similarly, the addition of wortmannin or LY294002 to cells expressing the wild-type PDGFR inhibited the release of intracellular calcium. Thus, generation of PtdIns-3,4,5-P 3 by receptor-associated PI3K causes an increase in IP 3 production and intracellular calcium release, potentially via enhanced PtdIns-4,5-P 2 substrate availability due to PtdIns-3,4,5-P 3 -mediated recruitment of PLC␥ to the lipid bilayer.Activation of the receptor-associated phosphoinositide 3-kinase (PI3K) 1 has been shown to cause mitogenesis and enhanced cell motility, although the exact mechanism by which PI3K mediates cell signaling during these events has been difficult to elucidate (1-3). The lipid products of PI3K have now been found to activate certain calcium-independent protein kinases C and to bind to a subset of Src homology 2 (SH2) domains (4, 5). In addition, PtdIns-3,4-P 2 and/or PtdIns-3,4,5-P 3 has been found to bind to and/or stimulate several pleckstrin homology (PH) domain-containing proteins, including the Akt/PKB serine/threonine protein kinase (6, 7), the PDK serine/threonine protein kinase (8), and the Grp1 exchange factor for Arf1 (9). Falasca et al. (10) have demonstrated that the PH domain of phospholipase C␥ will bind to PtdIns-3,4,5-P 3 , targeting PLC␥ to the membrane.Recently, Bae et al. (11) have found that the addition of PtdIns-3,4,5-P 3 can enhance phospholipase C␥-mediated PtdIns-4,5-P 2 hydrolysis in vitro and that overexpression of a constitutively active form of the p110 catalytic subunit of PI3K increases intracellular IP 3 levels, raising the possibility that PtdIns-3,4,5-P 3 may regulate calcium signaling as well. This possibility is supported by the observation that wortmannin, an inhibitor of the catalytic site of PI3K, as well as several related enzymes, diminishes the intracellular calcium transient seen in adrenal glomerulosa cells, neutrophils, and rat leukemia cells following stimulation (12-15).To determine whether phospholipase C␥ might interact with the lipid products of PI3K in a manner capable of modifying ligand-dependent IP 3 generation and calcium sign...

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“…Precipitates were subjected to an in vitro kinase assay using g[ 32 P]ATP and phosphatidylinositol as substrates, according to Derman et al (1996). Brie¯y, beads were washed and incubated for 10 min at room temperature in kinase bu er containing 0.5 mM ATP, 20 mM MgCl 2 , 50 mM HEPES, pH 7.0, 0.25 mg/ml phosphatidylinositol and …”

Section: Pi3k Activitymentioning

confidence: 99%

VEGF165 requires extracellular matrix components to induce mitogenic effects and migratory response in breast cancer cells

et al. 2001

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An 11-Amino Acid Sequence from c-met Initiates Epithelial Chemotaxis via Phosphatidylinositol 3-Kinase and Phospholipase C

Cited by 58 publications

References 21 publications

Identification of Tyrosine Residues in Vascular Endothelial Growth Factor Receptor-2/FLK-1 Involved in Activation of Phosphatidylinositol 3-Kinase and Cell Proliferation

Identification of Tyrosine Residues in Vascular Endothelial Growth Factor Receptor-2/FLK-1 Involved in Activation of Phosphatidylinositol 3-Kinase and Cell Proliferation

Phosphoinositide 3-Kinase Regulates Phospholipase Cγ-mediated Calcium Signaling

VEGF165 requires extracellular matrix components to induce mitogenic effects and migratory response in breast cancer cells

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