Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) integrates developmental signals for eyelid closure
Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) integrates developmental signals for eyelid closure
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DOI：
10.1073/pnas.1102297108
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发表时间：
2011-10-18
影响因子：
11.1
通讯作者：
Xia, Ying
中科院分区：
文献类型：
--
作者：
Geh, Esmond;Meng, Qinghang;Xia, Ying
发育性眼睑闭合是进化上保守的形态发生事件，需要发育眼睑尖端的上皮细胞的增殖、分化、细胞骨架重组和迁移。许多信号事件发生在眼睑闭合过程中，但这些信号如何收敛以调节形态发生过程仍然是一个开放和有趣的问题。在这里，我们表明，丝裂原活化蛋白激酶1（MAP3K1）在发育中的眼睑上皮细胞中高度表达，与c-Jun形成，c-Jun是一种调节轴，通过整合两种不同的眼睑闭合信号网络来协调形态发生。TGF-α/EGFR-RhoA模块通过诱导c-Jun表达来启动这些网络之一，c-Jun以磷酸化非依赖性方式与Map3k1启动子结合并导致MAP3K1表达增加。RhoA基因敲除可通过降低MAP3K1的表达来干扰这一网络，并导致Map3K1半合子的眼睑闭合延迟。第二个网络由MAP 3K1的酶活性启动，其磷酸化并激活JNK-c-Jun模块，导致AP-1反式激活并诱导其下游基因，如派-1。MAP3K1失活降低了细胞和发育眼睑中的AP-1活性和PAI-1表达。因此，MAP3K1是在发育眼睑闭合中连接TGF-α/EGFR/RhoA-c-Jun和JNK-c-Jun-AP-1途径的内分泌调节环的联系。
Developmental eyelid closure is an evolutionarily conserved morphogenetic event requiring proliferation, differentiation, cytoskeleton reorganization, and migration of epithelial cells at the tip of the developing eyelid. Many signaling events take place during eyelid closure, but how the signals converge to regulate the morphogenetic process remains an open and intriguing question. Here we show that mitogen-activated protein kinase kinase kinase 1 (MAP3K1) highly expressed in the developing eyelid epithelium, forms with c-Jun, a regulatory axis that orchestrates morphogenesis by integrating two different networks of eyelid closure signals. A TGF-alpha/EGFR-RhoA module initiates one of these networks by inducing c-Jun expression which, in a phosphorylation-independent manner, binds to the Map3k1 promoter and causes an increase in MAP3K1 expression. RhoA knockout in the ocular surface epithelium disturbs this network by decreasing MAP3K1 expression, and causes delayed eyelid closure in Map3k1 hemizygotes. The second network is initiated by the enzymatic activity of MAP3K1, which phosphorylates and activates a JNK-c-Jun module, leading to AP-1 transactivation and induction of its downstream genes, such as Pai-1. MAP3K1 inactivation reduces AP-1 activity and PAI-1 expression both in cells and developing eyelids. MAP3K1 is therefore the nexus of an intracrine regulatory loop connecting the TGF-alpha/EGFR/RhoA-c-Jun and JNK-c-Jun-AP-1 pathways in developmental eyelid closure.