The interaction of IQGAP1 with the exocyst complex is required for tumor cell invasion downstream of Cdc42 and RhoA.
Invadopodia are actin-based membrane protrusions formed at contact sites between invasive tumor cells and the extracellular matrix with matrix proteolytic activity. Actin regulatory proteins participate in invadopodia formation, whereas matrix degradation requires metalloproteinases (MMPs) targeted to invadopodia. In this study, we show that the vesicle-tethering exocyst complex is required for matrix proteolysis and invasion of breast carcinoma cells. We demonstrate that the exocyst subunits Sec3 and Sec8 interact with the polarity protein IQGAP1 and that this interaction is triggered by active Cdc42 and RhoA, which are essential for matrix degradation. Interaction between IQGAP1 and the exocyst is necessary for invadopodia activity because enhancement of matrix degradation induced by the expression of IQGAP1 is lost upon deletion of the exocyst-binding site. We further show that the exocyst and IQGAP1 are required for the accumulation of cell surface membrane type 1 MMP at invadopodia. Based on these results, we propose that invadopodia function in tumor cells relies on the coordination of cytoskeletal assembly and exocytosis downstream of Rho guanosine triphosphatases.
Institut Curie, Centre de Recherche, Paris F-75248, France.
Mika
M
Sakurai-Yageta
Chiara
C
Recchi
Gaëlle
G
Le Dez
Jean-Baptiste
JB
Sibarita
Laurent
L
Daviet
Jacques
J
Camonis
Crislyn
C
D'Souza-Schorey
Philippe
P
Chavrier
D000199:Actins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005260:Female; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011554:Pseudopodia / Q000187:drug effects / Q000201:enzymology; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000199:Actins; D003432:Cross-Linking Reagents; D053511:Matrix Metalloproteinase 14; D050505:Mutant Proteins; D021122:Protein Subunits; D033921:Vesicular Transport Proteins; D020764:cdc42 GTP-Binding Protein; D020703:ras GTPase-Activating Proteins; D020742:rhoA GTP-Binding Protein; C489607:EXOC4 protein, human; C529992:EXOC1 protein, human; C101203:IQ motif containing GTPase activating protein 1