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Mol. Cell. Biol. doi:10.1128/MCB.00125-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Non-canonical Function of MEKK2 and MEK5 PB1 Domains for Coordinated ERK5 and JNK Signaling

Department of Pharmacology and Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365

^* To whom correspondence should be addressed. Email: gary_johnson{at}med.unc.edu.

	Abstract

MEKK2 and MEK5 encode Phox/Bem1p (PB1) domains that heterodimerize with one another. MEKK2, MEK5 and ERK5 form a ternary complex through interactions involving the MEKK2 and MEK5 PB1 domains and a 34 amino acid C-terminal extension of the MEK5 PB1 domain. This C-terminal extension encodes an ERK5 docking site required for MEK5 activation of ERK5. The PB1 domains bind in a front-to-back arrangement with a cluster of basic amino acids in the front of the MEKK2 PB1 domain binding to the back acidic clusters of the MEK5 PB1 domain. The C-terminal moiety including the acidic cluster of the MEKK2 PB1 domain is not required for MEK5 binding and binds MKK7. Quiescent MEKK2 preferentially binds MEK5 and MEKK2 activation results in ERK5 activation. Activated MEKK2 binds and activates MKK7 leading to JNK activation. The findings define how the MEKK2 and MEK5 PB1 domains are uniquely used for differential binding of two MAPK kinases, MEK5 and MKK7, for the coordinated control of ERK5 and JNK activation.

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