Department of Pathology, Moores University of California San Diego Cancer Center, La Jolla, CA 92093-1503, USA.
Oncogene. 2012 May 31;31(22):2783-93. doi: 10.1038/onc.2011.450. Epub 2011 Oct 3.
Tyrosine kinase receptors have an essential role in various aspects of tumor progression. In particular, epidermal growth factor receptor (EGFR) and its ligands have been implicated in the growth and dissemination of a wide array of human carcinomas. Here, we describe an EGFR-mediated signaling pathway that regulates human pancreatic carcinoma cell invasion and metastasis, yet does not influence the growth of primary tumors. In fact, ligation/activation of EGFR induces Src-dependent phosphorylation of two critical tyrosine residues of p130CAS, leading to the assembly of a Crk-associated substrate (CAS)/Nck1 complex that promotes Ras-associated protein-1 (Rap1) signaling. Importantly, GTP loading of Rap1 is specifically required for pancreatic carcinoma cell migration on vitronectin but not on collagen. Furthermore, Rap1 activation is required for EGFR-mediated metastasis in vivo without impacting primary tumor growth. These findings identify a molecular pathway that promotes the invasive/metastatic properties of human pancreatic carcinomas driven by EGFR.
酪氨酸激酶受体在肿瘤进展的各个方面都起着重要作用。特别是，表皮生长因子受体（EGFR）及其配体已被牵连到广泛的人类癌的生长和扩散。在这里，我们描述了一个 EGFR 介导的信号通路，它调节人类胰腺癌细胞的侵袭和转移，但不影响原发性肿瘤的生长。事实上，EGFR 的配体/激活导致 p130CAS 的两个关键酪氨酸残基的Src 依赖性磷酸化，导致 Crk 相关底物（CAS）/Nck1 复合物的组装，从而促进 Ras 相关蛋白-1（Rap1）信号。重要的是，Rap1 的 GTP 加载对于胰腺癌细胞在 vitronectin 上的迁移是特异性需要的，但在胶原蛋白上不需要。此外，Rap1 的激活对于 EGFR 介导的体内转移是必需的，而不影响原发性肿瘤的生长。这些发现确定了一个分子途径，该途径促进了由 EGFR 驱动的人类胰腺癌细胞的侵袭/转移特性。
