title: EGFR-dependent pancreatic carcinoma cell metastasis through Rap1 activation.
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.
authors.affiliation: Department of Pathology, Moores University of California San Diego Cancer Center, La Jolla, CA 92093-1503, USA.
authors.forename: M
authors.initials: M
authors.lastname: Huang
authors.forename: S
authors.initials: S
authors.lastname: Anand
authors.forename: E A
authors.initials: EA
authors.lastname: Murphy
authors.forename: J S
authors.initials: JS
authors.lastname: Desgrosellier
authors.forename: D G
authors.initials: DG
authors.lastname: Stupack
authors.forename: S J
authors.initials: SJ
authors.lastname: Shattil
authors.forename: D D
authors.initials: DD
authors.lastname: Schlaepfer
authors.forename: D A
authors.initials: DA
authors.lastname: Cheresh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002642:Chick Embryo; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D009362:Neoplasm Metastasis; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000556:secondary*; D034741:RNA, Small Interfering / Q000235:genetics; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C078332:Nck protein; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors