Selective targeting of MAPKs to the ETS domain transcription factor SAP-1

MAPK pathways play important roles in regulating the key cellular processes of proliferation, differentiation, and apoptosis, There are multiple MAPK pathways, which are subject to different regulatory cues. It is important t hat these pathways maintain specificity in sig naling to elicit the activat ion of a specific program of gene expression. MAPK-docking domains in sever al transcription factors have been shown to play important roles in determi ning the specificity and efficiency of their phosphorylation by MAPKs. Here we investigate the mechanisms by which MAPKs are targeted to the ETS domai n transcription factor SAP-I. We demonstrate that SAP-1 contains two differ ent domains that are required for its efficient phosphorylation in vitro an d activation in vivo by ERK2 and a subset of p38 MAPKs. The D-domain is clo sely related to other MAPK-docking domains, but exhibits a novel specificit y and serves to promote selective targeting of ERK2, p38 alpha, and p38 bet a (2) to SAP-1. A second important region, the FXF motif, also plays an imp ortant role in directing MAPKs to phosphorylate SAP-1. The FXF motif promot es targeting by ERK2 and, to a lesser extent, p38 alpha, but not p38 beta ( 2). Our data therefore demonstrate that a modular system of motifs is respo nsible for directing specific MAPK subtypes to SAP-1, but also point to imp ortant distinctions in the mechanism of action of the D-domain and FXF moti f.