INTERACTIONS OF PHOSPHATIDYLINOSITOL KINASE, GTPASE-ACTIVATING PROTEIN (GAP), AND GAP-ASSOCIATED PROTEINS WITH THE COLONY-STIMULATING FACTOR-I RECEPTOR

被引:159
作者
REEDIJK, M
LIU, XQ
PAWSON, T
机构
[1] MT SINAI HOSP, SAMUEL LUNENFELD RES INST, DIV MOLEC & DEV BIOL, 600 UNIV AVE, TORONTO M5G 1X5, ONTARIO, CANADA
[2] UNIV TORONTO, DEPT MED GENET, TORONTO M5S 1A8, ONTARIO, CANADA
关键词
D O I
10.1128/MCB.10.11.5601
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The interactions of the macrophage colony-stimulating factor 1 (CSF-1) receptor with potential targets were investigated after ligand stimulation either of mouse macrophages or of fibroblasts that ectopically express mouse CSF-1 receptors. In Rat-2 cells expressing the mouse CSF-1 receptor, full activation of the receptor and cellular transformation require exogenous CSF-1, whereas NIH 3T3 cells expressing mouse c-fms are transformed by autocrine stimulation. Activated CSF-1 receptors physically associate with a phosphatidylinositol (PI) 3′-kinase. A mutant CSF-1 receptor with a deletion of the kinase insert region was deficient in its ability to bind functional PI 3′-kinase and to induce PI 3′-kinase activity precipitable with antiphosphotyrosine antibodies. In fibroblasts, CSF-1 stimulation also induced the phosphorylation of the GTPase-activating protein (GAP)-associated protein p62 on tyrosine, although GAP itself was a relatively poor substrate. In contrast to PI 3′-kinase association, phosphorylation of p62 and GAP was not markedly affected by deletion of the kinase insert region. These results indicate that the kinase insert region selectively enhances the CSF-1-dependent association of the CSF-1 receptor with active PI 3′-kinase. The insert deletion mutant retains considerable transforming activity in NIH 3T3 cells (G. Taylor, M. Reedijk, V. Rothwell, L. Rohrschneider, and T. Pawson, EMBO J. 8:2029-2037, 1989). This mutant was more seriously impaired in Rat-2 cell transformation, although mutant-expressing Rat-2 cells still formed small colonies in soft agar in the presence of CSF-1. Therefore, phosphorylation of GAP and p62 through activation of the CSF-1 receptor does not result in full fibroblast transformation. The interaction between the CSF-1 receptor and PI 3′-kinase may contribute to c-fms fibroblast transformation and play a role in CSF-1-stimulated macrophages.
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收藏
页码:5601 / 5608
页数:8
相关论文
共 51 条
[1]   PDGF-DEPENDENT TYROSINE PHOSPHORYLATION STIMULATES PRODUCTION OF NOVEL POLYPHOSPHOINOSITIDES IN INTACT-CELLS [J].
AUGER, KR ;
SERUNIAN, LA ;
SOLTOFF, SP ;
LIBBY, P ;
CANTLEY, LC .
CELL, 1989, 57 (01) :167-175
[2]   THE PROTO-ONCOGENE C-KIT ENCODING A TRANSMEMBRANE TYROSINE KINASE RECEPTOR MAPS TO THE MOUSE W-LOCUS [J].
CHABOT, B ;
STEPHENSON, DA ;
CHAPMAN, VM ;
BESMER, P ;
BERNSTEIN, A .
NATURE, 1988, 335 (6185) :88-89
[3]  
COUGHLIN SR, 1989, SCIENCE, V243, P1191
[4]   AN 81-KD PROTEIN COMPLEXED WITH MIDDLE T-ANTIGEN AND PP60C-SRC - A POSSIBLE PHOSPHATIDYLINOSITOL KINASE [J].
COURTNEIDGE, SA ;
HEBER, A .
CELL, 1987, 50 (07) :1031-1037
[5]   PHOSPHOLIPASE C-GAMMA A SUBSTRATE FOR PDGF RECEPTOR KINASE, IS NOT PHOSPHORYLATED ON TYROSINE DURING THE MITOGENIC RESPONSE TO CSF-1 [J].
DOWNING, JR ;
MARGOLIS, BL ;
ZILBERSTEIN, A ;
ASHMUN, RA ;
ULLRICH, A ;
SHERR, CJ ;
SCHLESSINGER, J .
EMBO JOURNAL, 1989, 8 (11) :3345-3350
[6]   PHOSPHORYLATION OF GAP AND GAP-ASSOCIATED PROTEINS BY TRANSFORMING AND MITOGENIC TYROSINE KINASES [J].
ELLIS, C ;
MORAN, M ;
MCCORMICK, F ;
PAWSON, T .
NATURE, 1990, 343 (6256) :377-381
[7]   A PDGF RECEPTOR DOMAIN ESSENTIAL FOR MITOGENESIS BUT NOT FOR MANY OTHER RESPONSES TO PDGF [J].
ESCOBEDO, JA ;
WILLIAMS, LT .
NATURE, 1988, 335 (6185) :85-87
[8]   PHOSPHATIDYLINOSITOL KINASE-ACTIVITY ASSOCIATES WITH VIRAL P60SRC PROTEIN [J].
FUKUI, Y ;
HANAFUSA, H .
MOLECULAR AND CELLULAR BIOLOGY, 1989, 9 (04) :1651-1658
[9]   PDGF BETA-RECEPTOR STIMULATES TYROSINE PHOSPHORYLATION OF GAP AND ASSOCIATION OF GAP WITH A SIGNALING COMPLEX [J].
KAPLAN, DR ;
MORRISON, DK ;
WONG, G ;
MCCORMICK, F ;
WILLIAMS, LT .
CELL, 1990, 61 (01) :125-133
[10]   COMMON ELEMENTS IN GROWTH-FACTOR STIMULATION AND ONCOGENIC TRANSFORMATION - 85-KD PHOSPHOPROTEIN AND PHOSPHATIDYLINOSITOL KINASE-ACTIVITY [J].
KAPLAN, DR ;
WHITMAN, M ;
SCHAFFHAUSEN, B ;
PALLAS, DC ;
WHITE, M ;
CANTLEY, L ;
ROBERTS, TM .
CELL, 1987, 50 (07) :1021-1029