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Membrane‐Type 1 Matrix Metalloproteinase Downregulates Fibroblast Growth Factor‐2 Binding to the Cell Surface and Intracellular Signaling
Author(s) -
Tassone Evelyne,
Valacca Cristina,
Mignatti Paolo
Publication year - 2015
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24717
Subject(s) - microbiology and biotechnology , extracellular , intracellular , fibroblast growth factor , extracellular matrix , matrix metalloproteinase , fibroblast , cell , cytoplasm , downregulation and upregulation , signal transduction , cell surface receptor , 3t3 cells , transmembrane protein , cell membrane , biology , chemistry , receptor , cell culture , biochemistry , transfection , in vitro , genetics , gene
Membrane‐type 1 matrix metalloproteinase (MT1‐MMP, MMP‐14), a transmembrane proteinase with an extracellular catalytic domain and a short cytoplasmic tail, degrades extracellular matrix components and controls diverse cell functions through proteolytic and non‐proteolytic interactions with extracellular, intracellular, and transmembrane proteins. Here we show that in tumor cells MT1‐MMP downregulates fibroblast growth factor‐2 (FGF‐2) signaling by reducing the amount of FGF‐2 bound to the cell surface with high and low affinity. FGF‐2 induces weaker activation of ERK1/2 MAP kinase in MT1‐MMP expressing cells than in cells devoid of MT1‐MMP. This effect is abolished in cells that express proteolytically inactive MT1‐MMP but persists in cells expressing MT1‐MMP mutants devoid of hemopexin‐like or cytoplasmic domain, showing that FGF‐2 signaling is downregulated by MT1‐MMP proteolytic activity. MT1‐MMP expression results in downregulation of FGFR‐1 and ‐4, and in decreased amount of cell surface‐associated FGF‐2. In addition, MT1‐MMP strongly reduces the amount of FGF‐2 bound to the cell surface with low affinity. Because FGF‐2 association with low‐affinity binding sites is a prerequisite for binding to its high‐affinity receptors, downregulation of low‐affinity binding to the cell surface results in decreased FGF‐2 signaling. Consistent with this conclusion, FGF‐2 induction of tumor cell migration and invasion in vitro is stronger in cells devoid of MT1‐ MMP than in MT1‐MMP expressing cells. Thus, MT1‐MMP controls FGF‐2 signaling by a proteolytic mechanism that decreases the cell's biological response to FGF‐2. J. Cell. Physiol. 230: 366–377, 2015. © 2014 Wiley Periodicals, Inc.