期刊
EXPERIMENTAL CELL RESEARCH
卷 353, 期 2, 页码 88-99出版社
ELSEVIER INC
DOI: 10.1016/j.yexcr.2017.03.012
关键词
PRL-3/PTP4A3; Phosphatase; Integrin; Cell adhesion; Cell migration; Metastasis
资金
- Fondation de France [00012062]
- PIC Melanome Uveal - Institut Curie, Retina France
- CNRS (Centre National de la Recherche Scientifique) [UMR 3347]
- INSERM (Institut National de la Sante et de la Recherche Medicale) [U1021]
- Institut Curie and Universite Paris-Saclay, France
- French Ministere de l'Education Nationale, de l'Enseignement Superieur et de la Recherche
- Fondation ARC pour la Recherche sur le Cancer
In a previous transcriptomic analysis of 63 ocular melanomas of the uvea, we found that expression of the PRL-3/PTP4A3 gene, encoding a phosphatase that is anchored to the plasma membrane, was associated with the risk of metastasis, and a poor prognosis. We also showed that PRL-3 overexpression in OCM-1 ocular melanoma cells significantly increased cell migration in vitro and invasiveness in vivo, suggesting a direct role for PRL-3 in the metastatic spreading of uveal melanoma. Here, we aimed to identify PRL-3 substrates at the plasma membrane involved in adhesion to the extracellular matrix. We focused on integrin beta 1, which is the most highly expressed integrin in our cohort of uveal melanomas. We show that preventing PRL-3 anchorage to the plasma membrane i) abolishes PRL-3-induced migration in OCM-1 cells, ii) specifically enhances the spreading of OCM-1 cells overexpressing PRL-3, and favors the maturation of large focal adhesions (FAs) containing integrin beta 1 on collagen I. Knockdown experiments confirmed integrin Ill involvement in PRL3-induced migration. We identified interactions between PRL-3 and integrin beta 1, as well as with FAK P-Y397, an auto-activated form of Focal Adhesion Kinase found in FAs. We also show that integrin beta 1 may be dephosphorylated by PRL-3 in its intracytoplasmic S/T region, an important motif for integrin-mediated cell adhesion. Finally, we observed that PRL-3 regulated the clustering of integrin beta 1 in FAs on collagen I but not on fibronectin. This work identifies PRL-3 as a new regulator of cell adhesion structures to the extracellular matrix, and further supports PRL-3 as a key actor of metastasis in uveal melanoma, of which molecular mechanisms are still poorly understood.
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