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 that these pathways maintain specificity in signaling to elicit the activation of a specific program of gene expression. MAPK-docking domains in several transcription factors have been shown to play important roles in determining the specificity and efficiency of their phosphorylation by MAPKs. Here we investigate the mechanisms by which MAPKs are targeted to the ETS domain transcription factor SAP-1. We demonstrate that SAP-1 contains two different domains that are required for its efficient phosphorylation in vitro and activation in vivo by ERK2 and a subset of p38 MAPKs. The D-domain is closely related to other MAPK-docking domains, but exhibits a novel specificity and serves to promote selective targeting of ERK2, p38alpha, and p38beta(2) to SAP-1. A second important region, the FXF motif, also plays an important role in directing MAPKs to phosphorylate SAP-1. The FXF motif promotes targeting by ERK2 and, to a lesser extent, p38alpha, but not p38beta(2). Our data therefore demonstrate that a modular system of motifs is responsible for directing specific MAPK subtypes to SAP-1, but also point to important distinctions in the mechanism of action of the D-domain and FXF motif.
Galanis
A
A
School of Biological Sciences, University of Manchester, Manchester M13 9PT and the School of Biochemistry and Genetics, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom.
Yang
S H
SH
Sharrocks
A D
AD
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D017930:Genes, Reporter; D007700:Kinetics; D048669:MAP Kinase Kinase 6; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection; D050808:ets-Domain Protein Elk-4; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D050808:ets-Domain Protein Elk-4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6