A variety of metastatic cancer cells use actin-rich membrane protrusions, known as invadopodia, for efficient ECMdegradation, which involves trafficking of proteases from intracellular compartments to these structures. Here, wedemonstrate that in the metastatic breast cancer cell line MDA-MB-231, retromer regulates the matrix invasion activity byrecycling matrix metalloprotease, MT1-MMP. We further found that MT2-MMP, another abundantly expressedmetalloprotease, is also invadopodia associated. MT1- and MT2-MMP showed a high degree of colocalization but were locatedon the distinct endosomal domains. Retromer and its associated sorting nexin, SNX27, phenocopied each other in matrixdegradation via selectively recy... More
A variety of metastatic cancer cells use actin-rich membrane protrusions, known as invadopodia, for efficient ECMdegradation, which involves trafficking of proteases from intracellular compartments to these structures. Here, wedemonstrate that in the metastatic breast cancer cell line MDA-MB-231, retromer regulates the matrix invasion activity byrecycling matrix metalloprotease, MT1-MMP. We further found that MT2-MMP, another abundantly expressedmetalloprotease, is also invadopodia associated. MT1- and MT2-MMP showed a high degree of colocalization but were locatedon the distinct endosomal domains. Retromer and its associated sorting nexin, SNX27, phenocopied each other in matrixdegradation via selectively recycling MT1-MMP but not MT2-MMP. ITC-based studies revealed that both SNX27 and retromercould directly interact with MT1-MMP. Analysis from a publicly available database showed SNX27 to be overexpressed orfrequently altered in the patients having invasive breast cancer. In xenograft-based studies, SNX27-depleted cell linesshowed prolonged survival of SCID mice, suggesting a possible implication for overexpression of the sorting nexin in tumorsamples.
