Format

Send to

Choose Destination
Sci Rep. 2016 Apr 27;6:24925. doi: 10.1038/srep24925.

LIMK Regulates Tumor-Cell Invasion and Matrix Degradation Through Tyrosine Phosphorylation of MT1-MMP.

Author information

1
Institut Curie, PSL Research University, CNRS UMR 144, Membrane and Cytoskeleton Dynamics, 75248 cedex 05, Paris, France.
2
Univ. Grenoble Alpes, INSERM U823, Institut Albert Bonniot, CRI, Team 3 "Polarity, Development and Cancer", F-38000 Grenoble France.
3
Division of Cancer Studies, King's College London, London, United Kingdom.
4
Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.

Abstract

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.

PMID:
27116935
PMCID:
PMC4847008
DOI:
10.1038/srep24925
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center