Trusolino L, Bertotti A, Comoglio P M
IRCC, Institute for Cancer Research and Treatment, University of Torino School of Medicine, 10060 (Torino), Candiolo, Italy.
Cell. 2001 Nov 30;107(5):643-54. doi: 10.1016/s0092-8674(01)00567-0.
alpha6beta4 integrin and the Met receptor for HGF have been shown independently to promote invasive growth. We demonstrate here that Met selectively associates with alpha6beta4. In carcinoma cells expressing Met alone, HGF does not exert significant biological effects. Ectopic expression of alpha6beta4 restores HGF-regulated processes. Following Met activation, alpha6beta4 is tyrosine phosphorylated and combines with Shc and PI3K, generating an additional signaling platform that potentiates HGF-triggered activation of Ras- and PI3K-dependent pathways. In the presence of an alpha6beta4 mutant defective for Shc recruitment, Met cannot sustain HGF-mediated responses. Surprisingly, a truncated beta4 unable to bind laminins retains the activity of wild-type alpha6beta4. Such findings invoke an unexpected role for alpha6beta4 in cancer invasion as a functional amplifier of biochemical outputs rather than a mechanical adhesive device.
α6β4整合素和肝细胞生长因子（HGF）的Met受体已被独立证明可促进侵袭性生长。我们在此证明，Met选择性地与α6β4结合。在仅表达Met的癌细胞中，HGF不会发挥显著的生物学效应。α6β4的异位表达可恢复HGF调节的过程。Met激活后，α6β4发生酪氨酸磷酸化，并与Shc和PI3K结合，形成一个额外的信号平台，增强HGF触发的Ras和PI3K依赖性途径的激活。在存在缺陷于Shc募集的α6β4突变体的情况下，Met无法维持HGF介导的反应。令人惊讶的是，一个截短的无法结合层粘连蛋白的β4保留了野生型α6β4的活性。这些发现揭示了α6β4在癌症侵袭中作为生化输出的功能放大器而非机械粘附装置的意想不到的作用。
