Vav1 as a central regulator of invadopodia assembly

Gina Razidlo, Barbara Schroeder, Jing Chen, Daniel D Billadeau, Mark A Mc Niven

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)86-93
Number of pages8
JournalCurrent Biology
Volume24
Issue number1
DOIs
StatePublished - Jan 6 2014

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Cells
Tumors
Neoplasms
Phosphorylation
GTP Phosphohydrolases
guanosinetriphosphatase
cell movement
Cell Movement
phosphorylation
Cortactin
Chemical activation
Guanine Nucleotide Exchange Factors
pancreatic neoplasms
Degradation
rho GTP-Binding Proteins
degradation
src-Family Kinases
small interfering RNA
Pancreatic Neoplasms
extracellular matrix

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Vav1 as a central regulator of invadopodia assembly. / Razidlo, Gina; Schroeder, Barbara; Chen, Jing; Billadeau, Daniel D; Mc Niven, Mark A.

In: Current Biology, Vol. 24, No. 1, 06.01.2014, p. 86-93.

Research output: Contribution to journalArticle

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