THE SH3 DOMAIN-BINDING T-CELL TYROSYL PHOSPHOPROTEIN P120 - DEMONSTRATION OF ITS IDENTITY WITH THE C-CBL PROTOONCOGENE PRODUCT AND IN-VIVO COMPLEXES WITH FYN, GRB2, AND PHOSPHATIDYLINOSITOL 3-KINASE

被引:194
作者
FUKAZAWA, T
REEDQUIST, KA
TRUB, T
SOLTOFF, S
PANCHAMOORTHY, G
DRUKER, B
CANTLEY, L
SHOELSON, SE
BAND, H
机构
[1] HARVARD UNIV, BRIGHAM & WOMENS HOSP,SCH MED, DEPT RHEUMATOL & IMMUNOL,LYMPHOCYTE BIOL SECT, BOSTON, MA 02115 USA
[2] HARVARD UNIV, BRIGHAM & WOMENS HOSP,SCH MED,DEPT MED, JOSLIN DIABET CTR,RES DIV, BOSTON, MA 02115 USA
[3] HARVARD UNIV, BETH ISRAEL HOSP, SCH MED, DIV SIGNAL TRANSDUCT, BOSTON, MA 02115 USA
[4] HARVARD UNIV, SCH MED, DEPT CELL BIOL, BOSTON, MA 02115 USA
[5] OREGON HLTH SCI UNIV, DIV HEMATOL & MED ONCOL, PORTLAND, OR 97201 USA
关键词
D O I
10.1074/jbc.270.32.19141
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
Previously, we have identified p120 as a Fyn/Lck SH3 and SH2 domain-binding protein that is tyrosine phosphorylated rapidly after T cell receptor triggering. Here, we used direct protein purification, amino acid sequence analysis, reactivity with antibodies, and two-dimensional gel analyses to identify p120 as the human c-cbl protooncogene product. We demonstrate in, vivo complexes of p120(cbl) with Fyn tyrosine kinase, the adaptor protein Grb2, and the p85 subunit of phosphatidylinositol (PI) 3-kinase, The association of p120(cbl) with Fyn and the p85 subunit of PI 3-kinase (together with PI 3-kinase activity) was markedly increased by T cell activation, consistent with in vitro binding of p120(cbl) to their SH2 as well as SH3 domains, In contrast, a large fraction of p120(cbl) was associated with Grb2 prior to activation, and this association did not change upon T cell activation. In vitro, p120(cbl) interacted with Grb2 exclusively through its SH3 domains, These results demonstrate a novel Grb2-p120(cbl) signaling complex in T cells, distinct from the previously analyzed Grb2-Sos complex. The association of p120(cbl) with ubiquitous signaling proteins strongly suggests a general signal transducing function for this enigmatic protooncogene with established leukemogenic potential but unknown physiological function.
引用
收藏
页码:19141 / 19150
页数:10
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