Abstract
The cell signaling molecule MEK kinase 2 (MEKK2) is a key upstream regulator of MAPK activity that regulates numerous cellular functions, but the mechanisms that control MEKK2 activity are not well understood. Recently, we reported that MEKK2 both binds and promotes ubiquitylation of the scaffold protein paxillin, and thereby modulates the composition of adhesion complexes. In this study, we have extended our examination of this interaction and report that recombinant paxillin is sufficient to induce MEKK2 auto-phosphorylation. Furthermore, we utilize siRNA-mediated paxillin expression knockdown to reveal that MEKK2 activity is reduced in paxillin-deficient cells. Finally, we show that the paxillin leucine-rich motif 1 (LD1) is sufficient to bind to the MEKK2 amino terminal region and activate MEKK2. Taken together, our results show for the first time that paxillin association promotes MEKK2 activation and reveal the existence of a novel bi-directional regulatory relationship between MEKK2 and paxillin.
Highlights
MEK kinase 2 (MEKK2) is a serine-threonine kinase within the MAP kinase kinase kinase (MAP3K) group of intracellular signaling regulatory enzymes
Paxillin interaction induces MEKK2 auto-phosphorylation We previously reported that MEKK2 promotes paxillin ubiquitylation and that MEKK2 kinase activity is required for that function
As paxillin is a scaffold protein that does not display kinase activity, the MEKK2 phosphorylation observed must be due to auto-phosphorylation
Summary
MEKK2 is a serine-threonine kinase within the MAP kinase kinase kinase (MAP3K) group of intracellular signaling regulatory enzymes. MEKK2 activity controls activation of the JNK and ERK5 MAP kinases [1, 2], and as such is a component of a signaling node that regulates the expression and activity of multiple transcription factors, including activating protein 1 (AP1), NFkappa B, and MEF2C [3,4,5,6]. These factors, in turn, control the expression of numerous genes including cytokines and proteases [7,8,9,10]. We report our evidence of a bi-directional regulatory relationship between paxillin and MEKK2, and the novel role of the PB1 domain in that interaction
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