Modulation of the membrane type 1 matrix metalloproteinase cytoplasmic tail enhances tumor cell invasion and proliferation in three-dimensional collagen matrices.
Increasing evidence suggests that the cytoplasmic tail of membrane type 1 matrix metalloproteinase (MT1-MMP) is subject to phosphorylation and that this modification may influence its enzymatic activity at the cell surface. In this study, phosphorylated MT1-MMP is detected using a phospho-specific antibody recognizing a protein kinase C consensus sequence (phospho-TXR), and a MT1-MMP tail peptide is phosphorylated by exogenous protein kinase C. To characterize the potential role of cytoplasmic residue Thr(567) in these processes, mutants that mimic a state of either constitutive (T567E) or defective phosphorylation (T567A) were expressed and analyzed for their functional effects on MT1-MMP activity and cellular behavior. Phospho-mimetic mutants of Thr(567) exhibit enhanced matrix invasion as well as more extensive growth within a three-dimensional type I collagen matrix. Together, these findings suggest that MT1-MMP surface action is regulated by phosphorylation at cytoplasmic tail residue Thr(567) and that this modification plays a critical role in processes that are linked to tumor progression.
Moss
Natalie M
NM
Department of Cell and Molecular Biology, Northwestern University Feinberg Medical School, Chicago, Illinois 60611, USA.
Wu
Yi I
YI
Liu
Yueying
Y
Munshi
H G
HG
Stack
M Sharon
MS
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D024042:Collagen Type I / Q000737:chemistry / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017354:Point Mutation; D051381:Rats; D013912:Threonine / Q000032:analysis / Q000737:chemistry* / Q000235:genetics
D024042:Collagen Type I; D013912:Threonine; D053511:Matrix Metalloproteinase 14