Alpha 6 beta 4 signaling pathway

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). NetPath (http://www.netpath.org) is a collaborative project between PandeyLab at Johns Hopkins University (http://pandeylab.igm.jhmi.edu) and the Institute of Bioinformatics (http://www.ibioinformatics.org). If you use this pathway, please cite the NetPath website until the pathway is published.

整合素α6β4于20世纪80年代末由两组研究人员独立发现，分别被命名为αEβ4或Ic-Ic结合蛋白（Ic-IcBP）（1，2）。整合素α6β4是半桥粒（HDs）的组成部分（3，4，5）。研究发现，αEβ4表达的增加及其分布的改变与肿瘤侵袭性增强和不良预后密切相关（6，7）。尽管整合素α6β4可以与不同的层粘连蛋白异构体相互作用，但在表皮基底膜中，其首选配体为层粘连蛋白-5（8，9）。β4整合素是一种大型蛋白质，其细胞质域含有超过1000个氨基酸（10，11）。此域包含一个Na-Ca交换子（CalX）基序，其后紧接着两对III型纤连蛋白（FNIII）结构域，由连接段（CS）分隔。研究表明，它通过plectin和BP230与中间丝系统相联系，而plectin和BP230是半桥粒的组成部分（12，13，14）。整合素β4与半桥粒成分，包括plectin、BP230和BP180的相互作用，被发现对于与细胞生长、存活和迁移相关的生理和病理条件下的信号事件至关重要。研究表明，β4可以正向和负向调节角质形成细胞的迁移（15，16，17，18）。此外，它还发现可以通过PI3K/Akt通路依赖性方式调节细胞培养系统中的压力条件下角质形成细胞的存活（19，18）。然而，α6β4在体内并未发现对角质形成细胞存活有任何影响（20，18，16）。除了对角质形成细胞的影响外，证据表明整合素α6β4在癌细胞侵袭（21，22，23，24）和存活（25，26，27，28，16，29）中起着重要作用。癌细胞的侵袭通过IRS/PI3K依赖性过程进行调节，而对癌细胞存活的影响则通过PI3K/Akt依赖性方式进行。转录因子NFkappaB和NF-IL6在p38Mapk依赖性通路中的激活以及随后IL6基因表达的激活被证明是α6β4诱导的胸腺细胞存活和胸腺上皮细胞增殖的机制（27，30）。整合素α6β4还已知可激活Ras/Raf/MEK/ERK级联反应，该级联反应被发现参与细胞周期的调节（31，32，33，34）。NetPath（http://www.netpath.org）是约翰霍普金斯大学PandeyLab（http://pandeylab.igm.jhmi.edu）和生物信息学研究所（http://www.ibioinformatics.org）之间的合作项目。如使用此通路，请引用NetPath网站，直至通路发表。