title: Syntaxins 3 and 4 mediate vesicular trafficking of α5β1 and α3β1 integrins and cancer cell migration.
abstract: Integrins, a family of heterodimeric receptors for cell adhesion to the extracellular matrix (ECM), play key roles in cell migration, cancer progression and metastasis. As transmembrane proteins, integrins are transported in vesicles and delivered to the cell surface by vesicular trafficking. The final step for integrin delivery, i.e., fusion of integrin-containing vesicles with the plasma membrane, is poorly understood at the molecular level. The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins syntaxins 1, 2, 3 and 4 are present at the plasma membrane to drive vesicle fusion. In this study, we examined the roles of syntaxins 1, 2, 3 and 4 in vesicular trafficking of α5β1 and α3β1 integrins. We showed that syntaxins 2, 3 and 4 were expressed in HeLa cervical adenocarcinoma cells and PANC-1 pancreatic adenocarcinoma cells. In migrating HeLa and PANC-1 cells, syntaxins 2, 3 and 4 co-localized with the lipid raft constituent GM1 ganglioside at the leading edge. siRNA knockdown (KD) of syntaxins 3 and 4, but not of syntaxin 2, in HeLa cells reduced cell surface expression of α5β1 and α3β1 integrins and accumulated the integrins in cytoplasmic vesicles, indicating that syntaxins 3 and 4 mediate vesicular trafficking of α5β1 and α3β1 integrins to the cell surface. In addition, KD of syntaxins 3 and 4 inhibited cell adhesion to fibronectin, suppressed chemotactic cell migration and triggered apoptosis. Collectively, these data suggest that syntaxins 3- and 4-dependent integrin trafficking is important in cancer cell migration and survival, and may be a valuable target for cancer therapy.
authors: Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors: Paul
authors: P
authors: Day
authors: Krista A
authors: KA
authors: Riggs
authors: Nazarul
authors: N
authors: Hasan
authors: Deborah
authors: D
authors: Corbin
authors: David
authors: D
authors: Humphrey
authors: Chuan
authors: C
authors: Hu
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D039201:Integrin alpha3beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D050600:SNARE Proteins / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D039201:Integrin alpha3beta1; D039081:Integrin alpha5beta1; D050765:Qa-SNARE Proteins; D050600:SNARE Proteins