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EGFR-dependent pancreatic carcinoma cell metastasis through Rap1 activation

Oncogene volume 31, pages 2783–2793 (2012)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr Steven K Hanks for the donation of the CAS mutant plasmids and Dr David J Shields for helpful discussion. This work was supported by NIH Grants CA107263 (DGS), HL56595 and HL47900 (SJS), CA102310 (DDS), and CA045726 (DAC).

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Authors and Affiliations

  1. Department of Pathology, Moores University of California San Diego Cancer Center, La Jolla, CA, USA

    M Huang, S Anand, E A Murphy, J S Desgrosellier, D G Stupack & D A Cheresh

  2. Department of Medicine, University of California San Diego, La Jolla, CA, USA

    S J Shattil

  3. Reproductive Medicine, Moores University of California San Diego Cancer Center, La Jolla, CA, USA

    D D Schlaepfer

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  1. M Huang
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Correspondence to D A Cheresh.

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Huang, M., Anand, S., Murphy, E. et al. EGFR-dependent pancreatic carcinoma cell metastasis through Rap1 activation. Oncogene 31, 2783–2793 (2012). https://doi.org/10.1038/onc.2011.450

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