WP244 - Alpha 6 beta 4 signaling - Homo sapiens

The integrin alpha6beta4 was discovered in the late 1980s by two different groups and was called either alphaEbeta4 or Ic-Ic binding protein (Ic-IcBP) (1,2). The alpha6beta4 integrin is a component of Hemidesmosomes (HDs) (3, 4,5). Increased expression of alphaEbeta4 and changes in its distribution is found to be correlated with increased aggressiveness of tumors and poor prognosis (6, 7). Although integrin alpha6beta4, can interact with different laminin isoforms, its preferred ligand in the epidermal BM is laminin-5 (8, 9). The beta4 integrin is a large protein and has a cytoplasmic domain of more than 1000 amino acids (10, 11). This domain contains a Na-Ca exchanger (CalX) motif followed by two pairs of type III fibronectin (FNIII) domains separated by a connecting segment (CS). It is found to associate with the intermediate filament system through plectin and BP230, which are components of hemidesmosomes (12,13,14). Interaction of intgrin beta4 with components of hemidesmosomes including plectin, BP230 and BP180 is found to be important in signaling events associated with cell growth, survival, and migration under physiological and pathological conditions.

Studies have shown that beta4 can regulate keratinocyte migration both positively and negatively (15,16,17,18). It is also found to regulate cell survival in keratinocytes in cell culture systems under stress in a PI3K/Akt pathway dependent manner (19,18). However, alpha6beta4 was not found to have any effect on keratinocyte survival in vivo (20, 18, 16). Apart from its effects on keratinocytes, evidence suggests that integrin alpha6beta4 is important in cancer cell invasion (21,22,23,24) and survival (25,26,27,28,16,29). The cancer cell invasion is regulated through a IRS/PI3K dependent process while the effect on carcinoma cell survival in a PI3K/Akt and dependent manner. Activation of the transcription factors NFkappaB and NF-IL6 in a p38Mapk dependent pathway and subsequent activation of IL6 gene expression was shown to be mechanism of alpha6beta4 induced survival of thymocytes and proliferation of thymic epithelial cells (27,30). Integrin alpha6beta4 is also known activate the Ras/Raf/MEK/ERK cascade which is found to be involved in the regulation of cell cycle (31,32,33,34).
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整合素α6β4（integrin alpha6beta4）于20世纪80年代末被两个独立研究团队发现，曾被命名为αEβ4或Ic-Ic结合蛋白（Ic-IcBP）(1,2)。整合素α6β4是半桥粒（Hemidesmosomes）的组成成分(3,4,5)。研究发现，αEβ4的表达上调及其分布改变与肿瘤侵袭性增强及预后不良密切相关(6,7)。尽管整合素α6β4可与多种层粘连蛋白亚型结合，但其在表皮基底膜中的优选配体为层粘连蛋白-5(8,9)。β4整合素为大分子蛋白，其胞内结构域包含超过1000个氨基酸残基(10,11)。该结构域含有一个Na-Ca交换器（CalX）基序，随后是两对由连接区段（CS）分隔的III型纤连蛋白（FNIII）结构域。研究证实，它可通过半桥粒组分网蛋白（plectin）和BP230与中间丝系统相结合(12,13,14)。整合素β4与半桥粒组分（包括网蛋白、BP230及BP180）的相互作用，在生理及病理状态下的细胞生长、存活与迁移相关信号事件中发挥关键作用。

研究表明，β4可双向调控角质形成细胞的迁移(15,16,17,18)。在应激状态下的细胞培养体系中，它还可通过依赖于PI3K/Akt通路的方式调控角质形成细胞的存活(19,18)。然而，在体内环境中，整合素α6β4未被发现对角质形成细胞存活具有任何影响(20,18,16)。除对角质形成细胞的调控作用外，有证据显示整合素α6β4在癌细胞侵袭(21,22,23,24)与存活(25,26,27,28,16,29)过程中具有重要功能。癌细胞侵袭通过依赖于IRS/PI3K的通路进行调控，而其对癌细胞存活的影响则依赖于PI3K/Akt通路。研究证实，转录因子核因子κB（NFkappaB）与核因子IL-6（NF-IL6）的激活依赖于p38丝裂原活化蛋白激酶（p38Mapk）通路，后续伴随IL6基因表达的上调，这一机制被认为是整合素α6β4诱导胸腺细胞存活及胸腺上皮细胞增殖的途径(27,30)。整合素α6β4还可激活Ras/Raf/MEK/ERK级联反应，该级联反应参与细胞周期的调控(31,32,33,34)。

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