A regulatory role for p38δ MAPK in keratinocyte differentiation -: Evidence for p38δ-ERK1/2 complex formation
A regulatory role for p38δ MAPK in keratinocyte differentiation -: Evidence for p38δ-ERK1/2 complex formation
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DOI：
10.1074/jbc.m302759200
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发表时间：
2003-09-05
影响因子：
4.8
通讯作者：
Eckert, RL
中科院分区：
文献类型：
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作者：
Efimova, T;Broome, AM;Eckert, RL
p38 MAPK亚型在多种细胞过程的调节中是重要的。在四种描述的p38同种型中，p38 α、β和δ在角质形成细胞中表达（Dashti，S. R.，Efimova，T.，和Eckert，R. L.（2001）J.Biol.Chem.276，8059 - 8063）。然而，很少有人知道个别p38亚型如何调节角质形成细胞的功能。在本研究中，我们使用冈田酸（OA）作为工具来研究p38 MAPKs作为角质形成细胞分化调节因子的作用。我们证明OA激活p38 δ，但不激活其他p38亚型。p38 δ激活早在OA添加后0.5 h就增加，并且在8和24 h时活性最大。ERK 1和ERK 2活性在相同的时间过程中降低。我们发现p38 delta与ERK 1/2形成复合物，并且p38 delta的过表达抑制ERK 1/2活性而不降低ERK 1/2水平。因此，p38 δ可能直接抑制ERK 1/2活性。进一步的研究表明，p38 δ在表皮中表达，表明p38 δ在调节分化中的作用。为了评估其功能，我们表明，增加p38 δ活性与AP 1和CAATT增强子结合蛋白因子的水平增加，这些因子与外皮蛋白（hINV）启动子的结合增加，表达增加。此外，这些反应在SB 203580的存在下得以维持，SB 203580是一种抑制p38 α和β的药物，进一步表明p38 δ亚型的核心作用。显性负性p38也抑制这些反应。这些独特的观察结果表明，p38 delta是驱动基底上hINV基因表达的主要p38亚型，并且p38 delta通过形成p38 delta-ERK 1/2复合物直接调节ERK 1/2活性。
p38 MAPK isoforms are important in the regulation of a variety of cellular processes. Among the four described p38 isoforms, p38alpha, beta, and delta are expressed in keratinocytes (Dashti, S. R., Efimova, T., and Eckert, R. L. (2001) J. Biol. Chem. 276, 8059 - 8063). However, very little is known about how individual p38 isoforms regulate keratinocyte function. In the present study, we use okadaic acid (OA) as a tool to study the role of p38 MAPKs as regulators of keratinocyte differentiation. We demonstrate that OA activates p38delta but not other p38 isoforms. p38delta activation is increased as early as 0.5 h after OA addition, and activity is maximal at 8 and 24 h. ERK1 and ERK2 activity are reduced on an identical time course. We show that p38delta forms a complex with ERK1/2, and overexpression of p38delta inhibits ERK1/2 activity without reducing ERK1/2 level. Thus, p38delta may directly suppress ERK1/2 activity. Additional studies show that p38delta is expressed in the epidermis, suggesting a role for p38delta in regulating differentiation. To evaluate its function, we show that increased p38delta activity is associated with increased levels of AP1 and CAATT enhancer binding protein factors, increased binding of these factors to the involucrin (hINV) promoter, and increased expression. Moreover, these responses are maintained in the presence of SB203580, an agent that inhibits p38alpha and beta, further suggesting a central role for the p38delta isoform. Dominant-negative p38 also inhibits these responses. These unique observations suggest that p38delta is the major p38 isoform driving suprabasal hINV gene expression and that p38delta directly regulates ERK1/2 activity via formation of a p38delta-ERK1/2 complex.