Post-translational modification of the membrane type 1 matrix metalloproteinase (MT1-MMP) cytoplasmic tail impacts ovarian cancer multicellular aggregate dynamics

Abstract

Membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14) is a transmembrane collagenase highly expressed in metastatic ovarian cancer and correlates with poor survival. Accumulating evidence shows that the cytoplasmic tail of MT1-MMP is subjected to phosphorylation, and this post-translational modification regulates enzymatic activity at the cell surface. To investigate the potential role of MT1-MMP cytoplasmic residue Thr phosphorylation in regulation of metastasis-associated behaviors, ovarian cancer cells that express low endogenous levels of MT1-MMP were engineered to express wild-type MT1-MMP, a phosphomimetic mutant (T567E), or a phosphodeficient mutant (T567A). Results show that Thr modulation influences behavior of both individual cells and multicellular aggregates (MCAs). The acquisition of either wild-type or mutant MT1-MMP expression results in altered cohesion of epithelial sheets and the formation of more compact MCAs relative to parental cells. Cells expressing MT1-MMP-T567E phosphomimetic mutants exhibit enhanced cell migration. Furthermore, MCAs formed from MT1-MMP-T567E-expressing cells adhere avidly to both intact peritoneal explants and three-dimensional collagen gels. Interaction of these MCAs with peritoneal mesothelium disrupts mesothelial integrity, exposing the submesothelial collagen matrix on which MT1-MMP-T567E MCAs rapidly disperse. Together, these findings suggest that post-translational regulation of the Thr in the MT1-MMP cytoplasmic tail may function as a regulatory mechanism to impact ovarian cancer metastatic success.

Effects of Modulating Actin Dynamics on HER2 Cancer Cell Motility and Metastasis

“…Dynactin also participates in vesicular trafficking of matrix metalloproteinase-14 (MT1-MMP or MMP-14) 40 . Given the involvement of MMP-14 in HER2+ cancer cell invasion 41 – 43 , it will be interesting to test for the effects of Myc B on Dynactin and MMP-14 activity in these models in future studies aimed at understanding comprehensive effects of actin disruption in metastatic cancers.…”

Post-Translational Modification-Dependent Activity of Matrix Metalloproteinases

“…A study by Moss et al showed that phospho-mimetic Thr 567 mutants exhibit higher collagenolytic activity and three-dimensional growth within a collagen matrix, thereby promoting enhanced matrix invasion in ovarian cancer cells [88]. In addition, phosphorylation of Thr 567 impacted the integrity of cell monolayer, cell motility and multicellular aggregate dynamics in ovarian cancer cells, promoting metastasis-associated behaviors [89]. Furthermore, a study by Nyalendo et al reported that phosphorylation at Tyr 573 influenced cell migration, suggested by the ability of a phospho-defective mutant to inhibit migration of cells endogenously expressing MMP14 [90].…”

The Many Facets of Metzincins and Their Endogenous Inhibitors: Perspectives on Ovarian Cancer Progression

“…MMP-9 is expressed by primary ovarian carcinoma cells derived from the ovary, metastatic implants and ascites [ 194 ]. A recent study has revealed that MT1-MMP is one of the MMPs that contribute to the detachment of multicellular aggregates floating in the ascites microenvironment [ 195 ]. MMP-2 is also found to be abundantly expressed by the multicellular aggregates derived from ascites and is thought to play a major role in early metastasis by facilitating the rapid disaggregation of the ovarian cancer cells for adhesion to the mesothelial surface [ 196 ].…”