Platelet-derived growth factor (PDGF) induction of egr-1 is independent of PDGF receptor autophosphorylation on tyrosine.

Autophosphorylation of the platelet-derived growth factor (PDGF) receptor on tyrosine, which is dependent upon and occurs immediately after ligand binding, has been linked to the activation of second messenger pathways thought to be necessary for the induction of gene expression, DNA synthesis, and mitogenesis.W e have investigated PDGF signal transduction in Balb/c-3T3 and MH-3T3 cells at the level of immediate-early gene induction under three conditions in which PDGF receptor autophosphorylation in response to PDGF binding is blocked cells transformed by v-rusKi, cells transformed by v-mos, and cells treated with genistein, a specific inhibitor of tyrosine kinases.PDGF induction of immediate-early genes c-myc, c-fos, and JE is blocked in these systems.Induction of another immediate-early gene, egr-I, occurs normally despite the absence of measurable tyrosine kinase activity.The s a m e results were obtained when cells were stimulated with PDGF-AA or PDGF-BB.It is not yet clear if this receptor tyrosine kinase-independent signal utilizes known PDGF second messengers, but these results demonstrate a new arm of the PDGF signal transduction pathway which operates in the absence of, and independently from, autophosphorylation of the receptor on tyrosine.The 180-kDa platelet-derived growth factor receptor (PDGF-R)' is a member of the family of transmembrane receptors with intrinsic tyrosine kinase activity.Upon binding of its ligand, the PDGF-R dimerizes and, like all receptors in this family, autophosphorylates multiple tyrosine residues in its intracellular domain (for reviews see Ullrich and Schlessinger, 1990;Glenney, 1992;Williams, 1989).Intracellular signaling seems to be initiated in large part by this autokinase activity, since cells expressing receptors with inactivated kinases (either by mutation or chemical inhibitors) do not undergo mitogenesis in response to PDGF (Fantl et al., 1989; Zwiller et al., 1991; Williams, 1989).Phosphorylation of particular receptor tyrosine residues has been shown to create high affinity binding sites for specific proteins containing src homology (SH-2) domains (Matsuda et al., 1990; Mayer et al., 1991; Anderson et al., 1990).Some of these proteins are enzymes that, through association * The costs of publication of this article were defrayed in part by the payment of page charges.