The interactome of metabolic enzyme carbonic anhydrase IX reveals novel roles in tumor cell migration and invadopodia/MMP14-mediated invasion.

Carbonic anhydrase IX (CAIX) is a hypoxia inducible factor 1-induced, cell surface pH regulating enzyme with an established role in tumor progression and clinical outcome. However, the molecular basis of CAIX-mediated tumor progression remains unclear. Here, we have utilized proximity dependent biotinylation (BioID) to map the CAIX 'interactome' in breast ...
cancer cells in order to identify physiologically relevant CAIX-associating proteins with potential roles in tumor progression. High confidence proteins identified include metabolic transporters, ?1 integrins, integrin-associated protein CD98hc and matrix metalloprotease 14 (MMP14). Biochemical studies validate the association of CAIX with ?2?1 integrin, CD98hc and MMP14, and immunofluorescence microscopy demonstrates colocalization of CAIX with ?2?1 integrin and MMP14 in F-actin/cofilin-positive lamellipodia/pseudopodia, and with MMP14 to cortactin/Tks5-positive invadopodia. Modulation of CAIX expression and activity results in significant changes in cell migration, collagen degradation and invasion. Mechanistically, we demonstrate that CAIX associates with MMP14 through potential phosphorylation residues within its intracellular domain, and that CAIX enhances MMP14-mediated collagen degradation by directly contributing hydrogen ions required for MMP14 catalytic activity. These findings establish hypoxia-induced CAIX as a novel metabolic component of cellular migration and invasion structures, and provide new mechanistic insights into its role in tumor cell biology.
Mesh Terms:
Animals, Antigens, Neoplasm, Breast Neoplasms, Carbonic Anhydrase IX, Cell Line, Tumor, Cell Movement, Female, HEK293 Cells, Humans, MCF-7 Cells, Mammary Neoplasms, Experimental, Matrix Metalloproteinase 14, Mice, Podosomes, Transfection
Oncogene
Date: Dec. 09, 2016
Download Curated Data For This Publication
220322
Switch View:
  • Interactions 181