Sehgal Bernd U, DeBiase Phillip J, Matzno Sumio, Chew Teng-Leong, Claiborne Jessica N, Hopkinson Susan B, Russell Alan, Marinkovich M Peter, Jones Jonathan C R
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
J Biol Chem. 2006 Nov 17;281(46):35487-98. doi: 10.1074/jbc.M606317200. Epub 2006 Sep 14.
Whether alpha6beta4 integrin regulates migration remains controversial. beta4 integrin-deficient (JEB) keratinocytes display aberrant migration in that they move in circles, a behavior that mirrors the circular arrays of laminin (LM)-332 in their matrix. In contrast, wild-type keratinocytes and JEB keratinocytes, induced to express beta4 integrin, assemble laminin-332 in linear tracks over which they migrate. Moreover, laminin-332-dependent migration of JEB keratinocytes along linear tracks is restored when cells are plated on wild-type keratinocyte matrix, whereas wild-type keratinocytes show rotation over circular arrays of laminn-332 in JEB keratinocyte matrix. The activities of Rac1 and the actin cytoskeleton-severing protein cofilin are low in JEB keratinocytes compared with wild-type cells but are rescued following expression of wild-type beta4 integrin in JEB cells. Additionally, in wild-type keratinocytes Rac1 is complexed with alpha6beta4 integrin. Moreover, Rac1 or cofilin inactivation induces wild-type keratinocytes to move in circles over rings of laminin-332 in their matrix. Together these data indicate that laminin-332 matrix organization is determined by the alpha6beta4 integrin/actin cytoskeleton via Rac1/cofilin signaling. Furthermore, our results imply that the organizational state of laminin-332 is a key determinant of the motility behavior of keratinocytes, an essential element of skin wound healing and the successful invasion of epidermal-derived tumor cells.
α6β4整合素是否调节细胞迁移仍存在争议。β4整合素缺陷型（JEB）角质形成细胞表现出异常迁移，即它们做圆周运动，这种行为反映了其基质中层粘连蛋白（LM）-332的圆形排列。相比之下，野生型角质形成细胞和诱导表达β4整合素的JEB角质形成细胞，会在它们迁移的线性轨迹上组装层粘连蛋白-332。此外，当细胞接种在野生型角质形成细胞基质上时，JEB角质形成细胞沿线性轨迹的层粘连蛋白-332依赖性迁移得以恢复，而野生型角质形成细胞在JEB角质形成细胞基质中的层粘连蛋白-332圆形阵列上会发生旋转。与野生型细胞相比，JEB角质形成细胞中Rac1和肌动蛋白细胞骨架切断蛋白丝切蛋白的活性较低，但在JEB细胞中表达野生型β4整合素后这些活性得到恢复。此外，在野生型角质形成细胞中，Rac1与α6β4整合素复合。而且，Rac1或丝切蛋白失活会诱导野生型角质形成细胞在其基质中的层粘连蛋白-332环上做圆周运动。这些数据共同表明，层粘连蛋白-332基质组织是由α6β4整合素/肌动蛋白细胞骨架通过Rac1/丝切蛋白信号传导决定的。此外，我们的结果表明，层粘连蛋白-332的组织状态是角质形成细胞运动行为的关键决定因素，而角质形成细胞运动行为是皮肤伤口愈合和表皮来源肿瘤细胞成功侵袭的重要因素之一。
