Csk-binding protein (Cbp) negatively regulates epidermal growth factor-induced cell transformation by controlling Src activation.
Epidermal growth factor receptor (EGFR) and Src tyrosine kinase cooperate in regulating EGFR-mediated cell signaling and promoting cell transformation and tumorigenesis in pathological conditions. Activation of Src is tightly regulated by the C-terminal Src kinase (Csk). The Csk-binding protein (Cbp) is a ubiquitously expressed transmembrane protein. Its functions include suppression of T-cell receptor activation through recruiting Csk and inhibiting Src family kinase (SFK). However, a potential role of Cbp in EGF-induced cell activities has not been investigated. Here, we report that EGF-stimulation-induced Cbp tyrosine phosphorylation followed by Cbp-Csk association, in a SFK-dependent manner. Expression of wild-type (wt) Cbp remarkably suppressed EGF-induced activation of Src, ERK1/2, and Akt-1 enzymes, and NIH3T3 cell transformation, as well as colony formation of a breast cancer cell line (MDA-MB-468) in soft agar. In contrast, expression of CbpY317F or knockdown endogenous Cbp in NIH3T3 cells by RNA interference significantly enhanced EGF-induced activation of these enzymes and cell transformation. In addition, overexpression of multiple receptor tyrosine kinases (RTKs)-induced Cbp tyrosine phosphorylation. These results demonstrate that Cbp functions as a negative regulator of cell transformation and tumor cell growth through downregulation of Src activation, suggesting that Cbp might be broadly involved in RTKs-activated signaling pathways and tumorigenesis.
Jiang
L Q
LQ
Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Feng
X
X
Zhou
W
W
Knyazev
P G
PG
Ullrich
A
A
Chen
Z
Z
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002352:Carrier Proteins / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003345:Corticosterone; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
D002352:Carrier Proteins; D051242:Caveolin 1; D011518:Proto-Oncogene Proteins; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; C000631346:CSK protein, human; D003345:Corticosterone