Noncanonical function of MEKK2 and MEK5 PB1 domains for coordinated extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase signaling.
MEKK2 and MEK5 encode Phox/Bem1p (PB1) domains that heterodimerize with one another. MEKK2, MEK5, and extracellular signal-related kinase 5 (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-end 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 mitogen-activated protein kinase kinases, MEK5 and MKK7, for the coordinated control of ERK5 and c-Jun N-terminal kinase activation.
Nakamura
Kazuhiro
K
Department of Pharmacology, 1108 Mary Ellen Jones Building, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, USA.
Johnson
Gary L
GL
D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D048671:MAP Kinase Kinase 5 / Q000737:chemistry*; D048688:MAP Kinase Kinase 7 / Q000502:physiology*; D048730:MAP Kinase Kinase Kinase 2 / Q000737:chemistry*; D051379:Mice; D018345:Mice, Knockout; D048054:Mitogen-Activated Protein Kinase 7 / Q000502:physiology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
D048054:Mitogen-Activated Protein Kinase 7; D048730:MAP Kinase Kinase Kinase 2; C482619:Map3k2 protein, mouse; D048671:MAP Kinase Kinase 5; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse