Vav1 as a Central Regulator of Invadopodia Assembly

Abstract

Summary 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 is 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.

Sos1 Regulates Macrophage Podosome Assembly and Macrophage Invasive Capacity

“…10,25,26). In particular, Vav proteins, GEFs for CdC42 and Rac, have been reported to regulate both myeloid cell podosomes (49,55) and invadopodia (56). Thus, it is tempting to speculate that Rho GTPases, and some of their GEFs, may actually act in an integrated more than redundant fashion, although only studies addressing this issue in the same cell type might elucidate this issue.…”

Cdc42 and Tks5

“…Cdc42-activating GEFs involved in invadosome formation include α-PIX/ArhGEF6, β-PIX/ArhGEF7, Fgd1, and Vav1. [48][49][50][51][52] However, as more than 70 Rho-GEFs are encoded in the human genome and as most are tissue-specific, the identity of the Cdc42-GEF may differ according to the cell type. Also, recently, other molecules such as palladin were shown to regulate Cdc42 activation.…”

Invadopodia and basement membrane invasion in vivo

“…The advantages in imaging, biochemical approaches, and genetic and pharmacological perturbations in 2D conditions have led to remarkable advances in our understanding of invadopodia. 22,[39][40][41][42] These findings include the identification of different components of invadopodia, [43][44][45] elucidation of the stages of invadopodia formation, [46][47][48][49] identification of genes associated with cancer metastasis that regulate invadopodia formation, 19,21,[50][51][52] understanding of the trafficking of proteases to invadopodia, [53][54][55][56][57] and examination of invadopodia membrane dynamics. 58 Key insights have also been gained into the regulation of their formation by growth factors, integrin activation, and the microenvironment, including hypoxia, matrix stiffness, Over 20 years ago, protrusive, F-actin-based membrane structures, termed invadopodia, were identified in highly metastatic cancer cell lines.…”