DNA-SYNTHESIS INDUCED BY SOME BUT NOT ALL GROWTH-FACTORS REQUIRES SRCFAMILY PROTEIN-TYROSINE KINASES

The Src family of protein tyrosine kinases have been implicated in the response of cells to several ligands. These include platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and colony stimul ating factor type 1 (CSF-1, in macrophages and in fibroblasts engineer ed to express the receptor). We recently described a microinjection ap proach which we used to demonstrate that Src family kinases are requir ed for PDGF-induced S phase entry of fibroblasts. We now use this appr oach to ask whether other ligands also require Src kinases to stimulat e cells to replicate DNA. An antibody specific for the carboxy terminu s of Src, Fyn, and Yes (anti-cst.1) inhibited Src kinase activity in v itro and caused morphological reversion of Src transformed cells in vi vo. Microinjection of this antibody was used to demonstrate that Src k inases, were required for both CSF-1 and EGF to drive cells into the S phase. Expression of a kinase inactive form of Src family kinases als o prevented EGF- and CSF-1-stimulated DNA synthesis. However, even tho ugh the Src family kinases were necessary for both PDGF- and EGF-induc ed DNA synthesis in Swiss 3T3 cells, the responses to two other potent growth factors for these cells, lysophosphatidic acid and bombesin, w ere unaffected by the neutralizing antibodies. Therefore, some but not all growth factors required functional Src family kinases to transmit mitogenic responses.