Dynamin 2 Potentiates Invasive Migration of Pancreatic Tumor Cells through Stabilization of the Rac1 GEF Vav1

Gina Razidlo, Yu Wang, Jing Chen, Eugene W. Krueger, Daniel D Billadeau, Mark A Mc Niven

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

The large GTPase Dynamin 2 (Dyn2) is markedly upregulated in pancreatic cancer, is a potent activator of metastatic migration, and is required for Rac1-mediated formation of lamellipodia. Here we demonstrate an unexpected mechanism of Dyn2 action in these contexts via direct binding to the Rac1 guanine nucleotide exchange factor (GEF) Vav1. Surprisingly, disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability. Importantly, a specific mutation in Vav1 near its Dyn2-binding C-terminal Src homology 3 (SH3) domain prevents Hsc70 binding, resulting in a stabilization of Vav1 levels. Dyn2 binding regulates the interaction of Vav1 with Hsc70 to control the stability and subsequent activity of this oncogenic GEF. These findings elucidate how Dyn2 activates Rac1, lamellipod protrusion, and invasive cellular migration and provide insight into how this specific Vav is ectopically expressed in pancreatic tumors.

Original languageEnglish (US)
Pages (from-to)573-585
Number of pages13
JournalDevelopmental Cell
Volume24
Issue number6
DOIs
StatePublished - Mar 25 2013

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Dynamin II
Guanine Nucleotide Exchange Factors
Tumors
Stabilization
Cells
Neoplasms
Cell Surface Extensions
Pseudopodia
src Homology Domains
Protein Stability
GTP Phosphohydrolases
Lysosomes
Pancreatic Neoplasms
Degradation
Mutation

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Dynamin 2 Potentiates Invasive Migration of Pancreatic Tumor Cells through Stabilization of the Rac1 GEF Vav1. / Razidlo, Gina; Wang, Yu; Chen, Jing; Krueger, Eugene W.; Billadeau, Daniel D; Mc Niven, Mark A.

In: Developmental Cell, Vol. 24, No. 6, 25.03.2013, p. 573-585.

Research output: Contribution to journalArticle

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