title: Vav1 as a central regulator of invadopodia assembly.
abstract: Invadopodia are protrusive structures used by tumor cells for degradation of the extracellular matrix to promote invasion [1]. Invadopodia formation and function are regulated by cytoskeletal-remodeling pathways and the oncogenic kinase Src. The guanine nucleotide exchange factor Vav1, which is an activator of Rho family GTPases, is ectopically expressed in many pancreatic cancers, where it promotes tumor cell survival and migration [2, 3]. We have now determined that Vav1 is also a potent regulator of matrix degradation by pancreatic tumor cells as depletion of Vav1 by siRNA-mediated knockdown inhibits the formation of invadopodia. This requires the exchange function of Vav1 toward the GTPase Cdc42, which is required for invadopodia assembly [4, 5]. In addition, we have determined that Src-mediated phosphorylation and activation of Vav1 are both required for, and, unexpectedly, sufficient for, invadopodia formation. Expression of Vav1 Y174F, which mimics its activated state, is a potent inducer of invadopodia formation through Cdc42, even in the absence of Src activation and phosphorylation of other Src substrates, such as cortactin. Thus, these data identify a novel mechanism by which Vav1 can enhance the tumorigenicity and invasive potential of cancer cells. These data suggest that Vav1 promotes the matrix-degrading processes underlying tumor cell migration and further, under conditions of ectopic Vav1 expression, that Vav1 is a central regulator and major driver of invasive matrix remodeling by pancreatic tumor cells.
authors: Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors: Gina L
authors: GL
authors: Razidlo
authors: Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors: Barbara
authors: B
authors: Schroeder
authors: Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors: Jing
authors: J
authors: Chen
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA; Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors: Daniel D
authors: DD
authors: Billadeau
authors: Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: mcniven.mark@mayo.edu.
authors: Mark A
authors: MA
authors: McNiven
mesh_terms: D005109:Extracellular Matrix / Q000378:metabolism; D005780:Gelatin / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051567:Proto-Oncogene Proteins c-vav; D034741:RNA, Small Interfering; C496618:VAV1 protein, human; D005780:Gelatin; D020764:cdc42 GTP-Binding Protein