LIMK Regulates Tumor-Cell Invasion and Matrix Degradation Through Tyrosine Phosphorylation of MT1-MMP.
During their metastatic spread, cancer cells need to remodel the extracellular matrix in order to migrate through stromal compartments adjacent to the primary tumor. Dissemination of breast carcinoma cells is mediated by membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), the main invadopodial matrix degradative component. Here, we identify MT1-MMP as a novel interacting partner of dual-specificity LIM Kinase-1 and -2 (LIMK1/2), and provide several evidence for phosphorylation of tyrosine Y573 in the cytoplasmic domain of MT1-MMP by LIMK. Phosphorylation of Y573 influences association of F-actin binding protein cortactin to MT1-MMP-positive endosomes and invadopodia formation and matrix degradation. Moreover, we show that LIMK1 regulates cortactin association to MT1-MMP-positive endosomes, while LIMK2 controls invadopodia-associated cortactin. In turn, LIMK1 and LIMK2 are required for MT1-MMP-dependent matrix degradation and cell invasion in a three-dimensional type I collagen environment. This novel link between LIMK1/2 and MT1-MMP may have important consequences for therapeutic control of breast cancer cell invasion.
Institut Curie, PSL Research University, CNRS UMR 144, Membrane and Cytoskeleton Dynamics, 75248 cedex 05, Paris, France.
Emilie
E
Lagoutte
Institut Curie, PSL Research University, CNRS UMR 144, Membrane and Cytoskeleton Dynamics, 75248 cedex 05, Paris, France.
Clémentine
C
Villeneuve
Univ. Grenoble Alpes, INSERM U823, Institut Albert Bonniot, CRI, Team 3 "Polarity, Development and Cancer", F-38000 Grenoble France.
Laurence
L
Lafanechère
Division of Cancer Studies, King's College London, London, United Kingdom.
Claire M
CM
Wells
Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
Gareth E
GE
Jones
Institut Curie, PSL Research University, CNRS UMR 144, Membrane and Cytoskeleton Dynamics, 75248 cedex 05, Paris, France.
Philippe
P
Chavrier
Institut Curie, PSL Research University, CNRS UMR 144, Membrane and Cytoskeleton Dynamics, 75248 cedex 05, Paris, France.
Carine
C
Rossé
D045744:Cell Line, Tumor; D002465:Cell Movement; D051356:Cortactin / Q000378:metabolism; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D014443:Tyrosine / Q000378:metabolism*
C495868:CTTN protein, human; D051356:Cortactin; D014443:Tyrosine; C515892:LIMK1 protein, human; C102895:LIMK2 protein, human; D054461:Lim Kinases; D053511:Matrix Metalloproteinase 14