The GTPase-activating Protein of Ras Suppresses Platelet-derived Growth Factor Beta Receptor Signaling by Silencing Phospholipase C-gamma 1

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 1995 Jun 1

PMID 7760802

Citations 16

Authors

M VALIUS

J P Secrist

A Kazlauskas

Affiliations

Soon will be listed here.

Abstract

The beta receptor for platelet-derived growth factor (beta PDGFR) is activated by binding of PDGF and undergoes phosphorylation at multiple tyrosine residues. The tyrosine-phosphorylated receptor associates with numerous SH2-domain-containing proteins which include phospholipase C-gamma 1 (PLC gamma), the GTPase-activating protein of Ras (GAP), the p85 subunit of phosphatidylinositol 3 kinase (PI3K), the phosphotyrosine phosphatase Syp, and several other proteins. Our previous studies indicated that PI3K and PLC gamma were required for relay of the mitogenic signal of beta PDGFR, whereas GAP and Syp did not appear to be required for this response. In this study, we further investigated the role of GAP and Syp in mitogenic signaling by beta PDGFR. Focusing on the PLC gamma-dependent branch of beta PDGFR signaling, we constructed a series of mutant beta PDGFRs that contained the binding sites for pairs of the receptor-associated proteins: PLC gamma and PI3K, PLC gamma and GAP, or PLC gamma and Syp. Characterization of these mutants showed that while all receptors were catalytically active and bound similar amounts of PLC gamma, they differed dramatically in their ability to initiate DNA synthesis. This signaling deficiency related to an inability to efficiently tyrosine phosphorylate and activate PLC gamma. Surprisingly, the crippled receptor was the one that recruited PLC gamma and GAP. Thus, GAP functions to suppress signal relay by the beta PDGFR, and it does so by silencing PLC gamma. These findings demonstrate that the biological response to PDGF depends not only on the ability of the beta PDGFR to recruit signal relay enzymes but also on the blend of these receptor-associated proteins.

Citing Articles

RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology.

Lei H, Qian C, Lei J, Haddock L, Mukai S, Kazlauskas A Mol Cell Biol. 2015; 35(10):1673-85.

PMID: 25733681 PMC: 4405646. DOI: 10.1128/MCB.01248-14.

Impaired Akt activity down-modulation, caspase-3 activation, and apoptosis in cells expressing a caspase-resistant mutant of RasGAP at position 157.

Yang J, Walicki J, Michod D, Dubuis G, Widmann C Mol Biol Cell. 2005; 16(8):3511-20.

PMID: 15901831 PMC: 1182293. DOI: 10.1091/mbc.e05-01-0080.

Partial cleavage of RasGAP by caspases is required for cell survival in mild stress conditions.

Yang J, Michod D, Walicki J, Murphy B, Kasibhatla S, Martin S Mol Cell Biol. 2004; 24(23):10425-36.

PMID: 15542850 PMC: 529026. DOI: 10.1128/MCB.24.23.10425-10436.2004.

Antiapoptotic signaling generated by caspase-induced cleavage of RasGAP.

Yang J, Widmann C Mol Cell Biol. 2001; 21(16):5346-58.

PMID: 11463818 PMC: 87258. DOI: 10.1128/MCB.21.16.5346-5358.2001.

Vav family proteins couple to diverse cell surface receptors.

Moores S, Selfors L, Fredericks J, Breit T, Fujikawa K, Alt F Mol Cell Biol. 2000; 20(17):6364-73.

PMID: 10938113 PMC: 86111. DOI: 10.1128/MCB.20.17.6364-6373.2000.

References

Yokote K, Mori S, Hansen K, McGlade J, Pawson T, Heldin C . Direct interaction between Shc and the platelet-derived growth factor beta-receptor. J Biol Chem. 1994; 269(21):15337-43. View

Ellis C, Moran M, McCormick F, Pawson T . Phosphorylation of GAP and GAP-associated proteins by transforming and mitogenic tyrosine kinases. Nature. 1990; 343(6256):377-81. DOI: 10.1038/343377a0. View

Chang J, Wilson L, Moyers J, Zhang K, Parsons S . Increased levels of p21ras-GTP and enhanced DNA synthesis accompany elevated tyrosyl phosphorylation of GAP-associated proteins, p190 and p62, in c-src overexpressors. Oncogene. 1993; 8(4):959-67. View

Traverse S, Seedorf K, PATERSON H, Marshall C, Cohen P, Ullrich A . EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Curr Biol. 1994; 4(8):694-701. DOI: 10.1016/s0960-9822(00)00154-8. View

Smith M, Liu Y, Kim H, Rhee S, Kung H . Inhibition of serum- and ras-stimulated DNA synthesis by antibodies to phospholipase C. Science. 1990; 247(4946):1074-7. DOI: 10.1126/science.2408147. View

Hafen E, Basler K, EDSTROEM J, Rubin G . Sevenless, a cell-specific homeotic gene of Drosophila, encodes a putative transmembrane receptor with a tyrosine kinase domain. Science. 1987; 236(4797):55-63. DOI: 10.1126/science.2882603. View

Nakanishi O, Shibasaki F, Hidaka M, Homma Y, Takenawa T . Phospholipase C-gamma 1 associates with viral and cellular src kinases. J Biol Chem. 1993; 268(15):10754-9. View

Nishibe S, Wahl M, Hernandez-Sotomayor S, Tonks N, Rhee S, Carpenter G . Increase of the catalytic activity of phospholipase C-gamma 1 by tyrosine phosphorylation. Science. 1990; 250(4985):1253-6. DOI: 10.1126/science.1700866. View

Roche S, Koegl M, Courtneidge S . The phosphatidylinositol 3-kinase alpha is required for DNA synthesis induced by some, but not all, growth factors. Proc Natl Acad Sci U S A. 1994; 91(19):9185-9. PMC: 44772. DOI: 10.1073/pnas.91.19.9185. View

10.

Brott B, Decker S, Shafer J, Gibbs J, Jove R . GTPase-activating protein interactions with the viral and cellular Src kinases. Proc Natl Acad Sci U S A. 1991; 88(3):755-9. PMC: 50892. DOI: 10.1073/pnas.88.3.755. View

11.

Ralston R, Bishop J . The product of the protooncogene c-src is modified during the cellular response to platelet-derived growth factor. Proc Natl Acad Sci U S A. 1985; 82(23):7845-9. PMC: 390866. DOI: 10.1073/pnas.82.23.7845. View

12.

Rhee S, Suh P, Ryu S, Lee S . Studies of inositol phospholipid-specific phospholipase C. Science. 1989; 244(4904):546-50. DOI: 10.1126/science.2541501. View

13.

Gould K, Hunter T . Platelet-derived growth factor induces multisite phosphorylation of pp60c-src and increases its protein-tyrosine kinase activity. Mol Cell Biol. 1988; 8(8):3345-56. PMC: 363570. DOI: 10.1128/mcb.8.8.3345-3356.1988. View

14.

Kazlauskas A, Feng G, Pawson T, VALIUS M . The 64-kDa protein that associates with the platelet-derived growth factor receptor beta subunit via Tyr-1009 is the SH2-containing phosphotyrosine phosphatase Syp. Proc Natl Acad Sci U S A. 1993; 90(15):6939-43. PMC: 47050. DOI: 10.1073/pnas.90.15.6939. View

15.

Li W, Nishimura R, Kashishian A, Batzer A, Kim W, Cooper J . A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase. Mol Cell Biol. 1994; 14(1):509-17. PMC: 358401. DOI: 10.1128/mcb.14.1.509-517.1994. View

16.

Bennett A, Tang T, Sugimoto S, WALSH C, Neel B . Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras. Proc Natl Acad Sci U S A. 1994; 91(15):7335-9. PMC: 44394. DOI: 10.1073/pnas.91.15.7335. View

17.

Marshall M, HILL W, Ng A, Vogel U, Schaber M, Scolnick E . A C-terminal domain of GAP is sufficient to stimulate ras p21 GTPase activity. EMBO J. 1989; 8(4):1105-10. PMC: 400921. DOI: 10.1002/j.1460-2075.1989.tb03480.x. View

18.

Ronnstrand L, Mori S, Arridsson A, Eriksson A, Wernstedt C, Hellman U . Identification of two C-terminal autophosphorylation sites in the PDGF beta-receptor: involvement in the interaction with phospholipase C-gamma. EMBO J. 1992; 11(11):3911-9. PMC: 556901. DOI: 10.1002/j.1460-2075.1992.tb05484.x. View

19.

Kashishian A, Kazlauskas A, Cooper J . Phosphorylation sites in the PDGF receptor with different specificities for binding GAP and PI3 kinase in vivo. EMBO J. 1992; 11(4):1373-82. PMC: 556586. DOI: 10.1002/j.1460-2075.1992.tb05182.x. View

20.

Buday L, Downward J . Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell. 1993; 73(3):611-20. DOI: 10.1016/0092-8674(93)90146-h. View