MEK7-dependent Activation of p38 MAP Kinase in Keratinocytes

Shervin R Dashti,Tatiana Efimova,Richard L Eckert

doi:10.1074/jbc.c000862200

Shervin R Dashti, Tatiana Efimova + Show 1 more

Open Access

https://doi.org/10.1074/jbc.c000862200

Copy DOI

Abstract

Previous studies suggest that a PKC/Ras/MEKK1 cascade regulates involucrin (hINV) gene expression in human epidermal keratinocytes. MEK7, which is expressed in epidermis, has been identified as a member of this cascade (Efimova, T., LaCelle, P., Welter, J. F., and Eckert, R. L. (1998) J. Biol. Chem. 273, 24387-24395 and Efimova, T., and Eckert, R. L. (2000) J. Biol. Chem. 275, 1601-1607). However, the kinase that functions downstream of MEK7 has not been identified. Our present studies show that MEK7 expression in keratinocytes markedly activates p38alpha and modestly activates JNK. Activation of p38 MAPK by MEK7 is a novel finding, as previous reports have assigned MEK7 as a JNK regulator. We also demonstrate that this regulation is physiologically important, as the p38alpha- and JNK-dependent activities regulate hINV promoter activity and expression of the endogenous hINV gene.

Highlights

Mitogen-activated protein kinase signal transduction pathways are three kinase modules that include MAPK1 kinase kinase (MEKK), mitogen-activated protein kinases (MAPK) kinase (MEK), and MAPK [1]
MEK7 Increases p38 MAPK Activity—To determine which MAPK is activated in the presence of MEK7, we delivered wild-type or constitutively active MEK7 to keratinocytes using adenovirus
In addition to the marked increase in p38 MAPK activity, caMEK7 produced a modest increase in JNK activity (3fold), but did not regulate ERK activity (Fig. 1C)

Summary

Introduction

Mitogen-activated protein kinase signal transduction pathways are three kinase modules that include MAPK1 kinase kinase (MEKK), MAPK kinase (MEK), and MAPK [1]. Activated MAPKs, in turn, translocate to the nucleus and phosphorylate nuclear transcription factors such as Elk-1 and AP1 [3, 4] These factors modulate gene expression by binding to DNA elements [5,6,7]. Previous studies from our laboratory indicate that MAPK cascades have a central role in the regulation of keratinocyte differentiation, as measured by the effects of activation of this cascade on the expression of a marker of keratinocyte differentiation, involucrin [6, 7]. This cascade, which includes the novel PKC isoforms, Ras, and MEKK1, activates involucrin expres-. These studies suggest that MEK7 increases hINV gene expression via activation of p38␣

Methods

Results

Conclusion