SNARE-dependent interaction of Src, EGFR and β1 integrin regulates invadopodia formation and tumor cell invasion.
Acquisition of an invasive phenotype is prerequisite for tumor metastasis. Degradation of the extracellular matrix (ECM), and subsequent invasion by tumor cells, is mediated, in part, through subcellular structures called invadopodia. Src-dependent cytoskeletal rearrangements are required to form invadopodia, and here we identify an association between Src, epidermal growth factor receptor (EGFR), and β1 integrin that facilitates invadopodia formation. The association of Src, EGFR and β1 integrin is dependent upon membrane traffic that is mediated by syntaxin13 (officially known as STX12) and SNAP23; a similar dependence on these two SNARE proteins was observed for invadopodium-based matrix degradation and cell invasion. Inhibition of SNARE function impaired the delivery of Src and EGFR to developing invadopodia, as well as the β1-integrin-dependent activation of Src and phosphorylation of EGFR on Tyr residue 845. We also identified an association between SNAP23 and β1 integrin, and inhibition of β1 integrin increased this association, whereas the interaction between syntaxin13 and SNAP23 was reduced. The results suggest that SNARE-dependent trafficking is regulated, in part, by β1 integrin and is required for the delivery of Src and EGFR to sites of invadopodia formation in order to support tumor cell invasion.
Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
Karla C
KC
Williams
Marc G
MG
Coppolino
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D066246:ErbB Receptors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000502:physiology*; D050766:Qb-SNARE Proteins / Q000502:physiology*; D050767:Qc-SNARE Proteins / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
D019012:Integrin beta1; D050765:Qa-SNARE Proteins; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; C100493:SNAP23 protein, human; C496151:STX12 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases
EGFR; Integrin; Invadopodia; SNARE; Src