α3β1 integrin promotes keratinocyte cell survival through activation of a MEK/ERK signaling pathway
α3β1 integrin promotes keratinocyte cell survival through activation of a MEK/ERK signaling pathway
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DOI：
10.1242/jcs.01277
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发表时间：
2004-08-15
影响因子：
4
通讯作者：
DiPersio, CM
中科院分区：
文献类型：
--
作者：
Manohar, A;Shome, SG;DiPersio, CM
上皮细胞与细胞外基质的不充分或不适当的粘附导致一种称为anoikis的凋亡形式。在各种组织重塑事件中，如伤口愈合或癌侵袭，物理性质和/或细胞外基质组成的变化可导致上皮细胞缺乏适当的受体-基质相互作用。Laminin-5是表皮角质形成细胞粘附的主要配体，在体内和体外也促进角质形成细胞的存活。整合素alpha3beta1和alpha6beta4是层粘连蛋白-5的主要受体；然而，这些整合素在角质形成细胞存活中的具体作用尚未确定。在目前的研究中，我们利用来自野生型或alpha3整合素敲除小鼠的角质细胞细胞系来揭示alpha3beta1在血清停药时保护角质细胞免于凋亡的关键作用。我们发现，alpha3beta1介导的与laminin-5细胞外基质的粘附抑制caspase-3的蛋白水解激活和tunel染色，这两者都是细胞凋亡的标志。我们还发现，alpha3beta1介导的粘附激活了局灶粘附激酶（FAK）和细胞外信号调节激酶（ERK），抑制FAK或ERK信号传导导致附着在层粘连蛋白5上的角化细胞凋亡。在缺乏alpha3beta1的情况下，alpha6beta1介导的与laminin-5的粘附仅能部分保护细胞免于凋亡，而在存在alpha3beta1的情况下，alpha6beta4对细胞存活并不是必需的。这些结果表明，alpha3beta1是最大限度的角化细胞在层粘连蛋白-5上存活的必要和充分条件。我们提出了一个模型来解决alpha3beta1介导的迁移角化细胞在皮肤伤口边缘存活的潜在重要性。
Inadequate or inappropriate adhesion of epithelial cells to extracellular matrix leads to a form of apoptosis known as anoikis. During various tissue remodelling events, such as wound healing or carcinoma invasion, changes in the physical properties, and/or composition of the extracellular matrix, can lead to anoikis of epithelial cells that lack appropriate receptor-matrix interactions. Laminin-5 is the major ligand for keratinocyte adhesion in the epidermis, and it also promotes keratinocyte survival in vivo and in vitro. Integrins alpha3beta1 and alpha6beta4 are the major receptors for laminin-5; however, specific roles for these integrins in keratinocyte survival have not been determined. In the current study, we exploited keratinocyte cell lines derived from wild-type or alpha3 integrin knockout mice to reveal a critical role for alpha3beta1 in protecting keratinocytes from apoptosis upon serum withdrawal. We show that alpha3beta1-mediated adhesion to laminin-5 extracellular matrix inhibits proteolytic activation of caspase-3 and TUNEL-staining, both hallmarks of apoptosis. We also show that alpha3beta1-mediated adhesion activates focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), and that inhibition of either FAK or ERK signaling leads to apoptosis of keratinocytes attached to laminin-5. alpha6beta4-mediated adhesion to laminin-5 only partially protects cells from apoptosis in the absence of alpha3beta1, and alpha6beta4 is not necessary for cell survival in the presence of alpha3beta1. These results suggest that alpha3beta1 is necessary and sufficient for maximal keratinocyte survival on laminin-5. We propose a model to address the potential importance of alpha3beta1-mediated survival for migrating keratinocytes at the leading edge of a cutaneous wound.