Department of Biochemistry/Molecular Biology and Medicine, Thoracic Diseases Research Unit, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, Minnesota 55905, USA.
J Biol Chem. 2011 May 20;286(20):17841-50. doi: 10.1074/jbc.M111.233676. Epub 2011 Mar 28.
TGF-β modulates numerous diverse cellular phenotypes including growth arrest in epithelial cells and proliferation in fibroblasts. Although the Smad pathway is fundamental for the majority of these responses, recent evidence indicates that non-Smad pathways may also have a critical role. Here we report a novel mechanism whereby the nonreceptor tyrosine focal adhesion kinase (FAK) functions as an adaptor necessary for cell type-specific responses to TGF-β. We show that in contrast to Smad actions, non-Smad pathways, including c-Abl, PAK2, and Akt, display an obligate requirement for FAK. Interestingly, this occurs in Src null SYF cells and is independent of FAK tyrosine phosphorylation, kinase activity, and/or proline-rich sequences in the C-terminal FAT domain. FAK binds the phosphatidylinositol 3-kinase (PI3K) p85 regulatory subunit following TGF-β treatment in a subset of fibroblasts but not epithelial cells and has an obligate role in TGF-β-stimulated anchorage-independent growth and migration. Together, these results uncover a new scaffolding role for FAK as the most upstream component regulating the profibrogenic action of TGF-β and suggest that inhibiting this interaction may be useful in treating a number of fibrotic diseases.
TGF-β 调节多种不同的细胞表型，包括上皮细胞的生长停滞和成纤维细胞的增殖。尽管 Smad 通路是大多数这些反应的基础，但最近的证据表明，非 Smad 通路也可能具有关键作用。在这里，我们报告了一种新的机制，即非受体酪氨酸焦点黏着激酶 (FAK) 作为衔接蛋白，对于 TGF-β 诱导的细胞类型特异性反应是必需的。我们表明，与 Smad 作用相反，非 Smad 通路，包括 c-Abl、PAK2 和 Akt，显示出对 FAK 的强制性需求。有趣的是，这发生在 Src 缺失的 SYF 细胞中，并且独立于 FAK 酪氨酸磷酸化、激酶活性和/或 C 端 FAT 结构域中的富含脯氨酸序列。FAK 在 TGF-β 处理后与磷酸肌醇 3-激酶 (PI3K) p85 调节亚基结合，但在部分成纤维细胞中而不是上皮细胞中，并且在 TGF-β 刺激的锚定非依赖性生长和迁移中具有强制性作用。这些结果揭示了 FAK 的新支架作用，作为调节 TGF-β 的促纤维化作用的最上游成分，并表明抑制这种相互作用可能对治疗多种纤维化疾病有用。
