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J. Biol. Chem., Vol. 280, Issue 51, 42051-42060, December 23, 2005

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Characterization of an ERK-binding Domain in Microphthalmia-associated Transcription Factor and Differential Inhibition of ERK2-mediated Substrate Phosphorylation^*

From the Department of Developmental and Cell Biology, University of California, Irvine, California 92697

Efficient and specific signaling by mitogen-activated protein kinases (MAPKs) is enhanced by docking sites found on many MAPK substrates and regulators. Here we show that the MAPKs ERK1 and ERK2 form a stable complex (K_d 6 µM) with their substrate the microphthalmia-associated transcription factor (MITF). Complex formation requires a domain of MITF of 100 residues that is nearby, but C-terminal to, the MAPK phosphorylation site at Ser⁷³. MITF derivatives lacking this ERK-binding domain do not bind ERK2 and are phosphorylated less efficiently by ERK2. The ERK-binding domain of MITF bears no obvious resemblance to previously characterized MAPK docking motifs; in particular, it does not contain a consensus D-site. Consistent with this, ERK2-MITF binding does not require the integrity of the CD/sevenmaker region of ERK2. Furthermore, D-site peptides, which are able to potently inhibit ERK2-mediated phosphorylation of the Elk-1 transcription factor (IC₅₀ = 3 µM), are relatively poor inhibitors of ERK2-mediated phosphorylation of MITF, exhibiting >15-fold selectivity for inhibition of Elk-1 versus MITF. These observations demonstrate substrate-selective kinase inhibition: the possibility that small molecules that target docking interactions may be used to selectively inhibit the phosphorylation of a subset of the substrates of a kinase.

Received for publication, September 27, 2005

^* This work was supported by NIGMS, National Institutes of Health Research Grant GM60366. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Tel.: 949-824-6902; Fax: 949-824-4709; E-mail: bardwell{at}uci.edu.

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