RAS MAP KINASE-DEPENDENT AND KINASE-INDEPENDENT SIGNALING PATHWAYS TARGET DISTINCT TERNARY COMPLEX FACTORS/

Transcriptional activation of the immediate early genes c-fos and egr- 1 by extracellular signals appears to be mediated by ternary complex f actors (TCFs). In BAC-1 macrophages, growth factor stimulation leads t o the retardation of protein-DNA complexes containing distinct TCFs. O ne TCF is recognized by Elk-1 antisera, whereas the other is immunolog ically related to SAP-1. The appearance and decay of hyperphosphorylat ed TCF/Elk-1-containing complexes after stimulation coincide with the activation of mitogen-activated protein kinase (MAPK) and the inductio n and repression of c-fos and egr-1, whereas modified TCF/SAP-1 contai ning complexes decay more slowly. Suppression of MAPK activation in ma crophages and fibroblasts correlates with the failure to induce TCF/El k-1 hyperphosphorylation without blocking TCF/SAP-1 modification. Acco rdingly the modified Elk-1 complex is generated in vitro by activated MAPK, whereas that of SAP-1 is not. Expression of a dominant-negative Ras mutant (Ras(Asn17)) in BAC-1 cells does not affect CSF-1 induced T CF/SAP-1 modification while suppressing TCF/Elk-1 phosphorylation. Nei ther PKC down-regulation by TPA nor inhibition of G(i) proteins by per tussis toxin pretreatment influences CSF-1 induced signaling to TCFs: one dependent on Ras and MAPK and converging on TCF/Elk-1, and the oth er targeting TCF/SAP-1 independently of RAS and MAPK.