title: Dynamin 2 potentiates invasive migration of pancreatic tumor cells through stabilization of the Rac1 GEF Vav1.
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.
authors.affiliation: Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Gina L
authors.initials: GL
authors.lastname: Razidlo
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Eugene W
authors.initials: EW
authors.lastname: Krueger
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.forename: Mark A
authors.initials: MA
authors.lastname: McNiven
mesh_terms: D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D034285:Dynamin II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D051567:Proto-Oncogene Proteins c-vav; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C496618:VAV1 protein, human; D020830:rac1 GTP-Binding Protein; D034285:Dynamin II
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