UC San Diego
EGFR-dependent pancreatic carcinoma cell metastasis via Rap1activation
- Author(s): Huang, Miller
- et al.
Tyrosine kinase receptors play 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. This has lead to the development of EGFR antagonists to treat patients with different types of tumors. However, the EGFR signaling cascade that promotes tumor metastasis is still unclear. Therefore, it is imperative to elucidate the mechanism of EGFR-dependent dissemination. The work in this dissertation characterizes an EGFR-mediated signaling pathway that selectively regulates human pancreatic carcinoma cell invasion and metastasis, without influencing the growth of primary tumors. Pancreatic cancer cells were examined for their invasive properties both in vitro and in vivo following EGFR stimulation. Biochemical studies were performed to analyze the signaling cascade downstream of EGFR that regulates tumor cell invasion and metastasis. I found that ligation/ activation of EGFR induces Src-dependent phosphorylation of two critical tyrosine residues of the adaptor protein, p130CAS, leading to assembly of a CAS/Nck1 complex that promotes Rap1 signaling. Importantly, GTP loading of Rap1 is specifically required for carcinoma cell migration on vitronectin, but not on collagen. Furthermore, Rap1 activation promotes spontaneous 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 the growth factor receptor, EGFR