TY - JOUR
T1 - Vav1 as a central regulator of invadopodia assembly
AU - Razidlo, Gina L.
AU - Schroeder, Barbara
AU - Chen, Jing
AU - Billadeau, Daniel D.
AU - McNiven, Mark A.
N1 - Funding Information:
We gratefully acknowledge the members of the McNiven lab for their contributions, in particular, Hong Cao and Eugene Krueger for technical assistance. This work was financially supported by grants from the National Cancer Institute (R01 CA104125 to M.A.M. and Pancreatic Cancer SPORE grant P50 CA102701 to D.D.B.) and the Optical Morphology Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology (NIDDK P30DK084567). G.L.R. was supported by grant T32 CA148073 from the National Institutes of Health.
PY - 2014/1/6
Y1 - 2014/1/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cub.2013.11.013
DO - 10.1016/j.cub.2013.11.013
M3 - Article
C2 - 24332539
AN - SCOPUS:84891834192
SN - 0960-9822
VL - 24
SP - 86
EP - 93
JO - Current Biology
JF - Current Biology
IS - 1
ER -