TRANSFORMING GROWTH-FACTOR-BETA DOWN-REGULATES SRC FAMILY PROTEIN-TYROSINE KINASE SIGNALING PATHWAYS

Transforming growth factor beta (TGF beta) inhibits the proliferation of a wide range of cell types through interaction with its cell surfac e receptor (R-TGF beta). R-TGF beta possesses serine/threonine kinase activity rather than the tyrosine kinase activity normally associated with peptide growth factor receptors; nevertheless, TGF beta triggers a signaling pathway that leads to the repression of transcription fact ors, which appear to mediate the action of receptor tyrosine kinases w ithin the nucleus. Accumulating evidence has also shown that the nonre ceptor protein tyrosine kinases of the Src family play essential roles in the signal transduction pathways that regulate cell proliferation, differentiation, and function. Here, we investigate whether signals i nitiated by R-TGF beta are transduced, at least in part, through membe rs of the Src family of tyrosine kinases. Treatment of the responsive human prostate carcinoma cell line PC3 with TGF beta induces a rapid a nd specific decrease in cellular levels of pp60(Src) and pp53/56(Lyn) and a corresponding decrease in their protein kinase activity when the assays were performed in vitro using the exogenous substrate enolase. Consistent with suppression of pp60(Src) and pp53/56(Lyn) kinase acti vity, TGF beta also caused a substantial intracellular accumulation of the unphosphorylated form of SH2-containing protein (SHC), a substrat e of the Src family kinases. This was paralleled by de creased formati on of a complex between the adaptor protein known as growth factor rec eptor-bound protein 2 and SHC. These results suggest, for the first ti me, that TGF beta induces down-regulation of Src family kinases, leadi ng to disruption of the SHC-growth factor receptor-bound protein 2 com plex. These events may play a crucial role in the negative regulation of Ras, as well as in the control of downstream effector molecules inv olved in the regulation of cell growth.