title: PRL-3/PTP4A3 phosphatase regulates integrin β1 in adhesion structures during migration of human ocular melanoma cells.
abstract: 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 β1, 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 iii) favors the maturation of large focal adhesions (FAs) containing integrin β1 on collagen I. Knockdown experiments confirmed integrin β1 involvement in PRL3-induced migration. We identified interactions between PRL-3 and integrin β1, as well as with FAK P-Y397, an auto-activated form of Focal Adhesion Kinase found in FAs. We also show that integrin β1 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 β1 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.
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR3347/INSERM U1021, Orsay, France; Université Paris Sud, Paris Saclay, Orsay France.
authors.forename: Malika
authors.initials: M
authors.lastname: Foy
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR3347/INSERM U1021, Orsay, France.
authors.forename: Océane
authors.initials: O
authors.lastname: Anézo
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR3347/INSERM U1021, Orsay, France; Université Paris Sud, Paris Saclay, Orsay France.
authors.forename: Simon
authors.initials: S
authors.lastname: Saule
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR3347/INSERM U1021, Orsay, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address: nathalie.planque@curie.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Planque
mesh_terms: D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics*; D005109:Extracellular Matrix / Q000235:genetics / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis* / Q000235:genetics; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis* / Q000235:genetics; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology; D000098943:Uveal Melanoma
chemical_list: D019012:Integrin beta1; D009363:Neoplasm Proteins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases
keywords: Cell adhesion; Cell migration; Integrin; Metastasis; PRL-3/PTP4A3; Phosphatase