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AXL confers cell migration and invasion by hijacking a PEAK1-regulated focal adhesion protein network.
Abu-Thuraia, Afnan; Goyette, Marie-Anne; Boulais, Jonathan; Delliaux, Carine; Apcher, Chloé; Schott, Céline; Chidiac, Rony; Bagci, Halil; Thibault, Marie-Pier; Davidson, Dominique; Ferron, Mathieu; Veillette, André; Daly, Roger J; Gingras, Anne-Claude; Gratton, Jean-Philippe; Côté, Jean-François.
Afiliação
  • Abu-Thuraia A; Montreal Clinical Research Institute (IRCM), Montréal, QC, H2W 1R7, Canada.
  • Goyette MA; Molecular Biology Programs, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
  • Boulais J; Montreal Clinical Research Institute (IRCM), Montréal, QC, H2W 1R7, Canada.
  • Delliaux C; Molecular Biology Programs, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
  • Apcher C; Montreal Clinical Research Institute (IRCM), Montréal, QC, H2W 1R7, Canada.
  • Schott C; Montreal Clinical Research Institute (IRCM), Montréal, QC, H2W 1R7, Canada.
  • Chidiac R; Montreal Clinical Research Institute (IRCM), Montréal, QC, H2W 1R7, Canada.
  • Bagci H; Molecular Biology Programs, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
  • Thibault MP; Montreal Clinical Research Institute (IRCM), Montréal, QC, H2W 1R7, Canada.
  • Davidson D; Molecular Biology Programs, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
  • Ferron M; Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC, H3C 3J7, Canada.
  • Veillette A; Montreal Clinical Research Institute (IRCM), Montréal, QC, H2W 1R7, Canada.
  • Daly RJ; Department of Anatomy and Cell Biology, McGill University, Montréal, QC, H3A 0C7, Canada.
  • Gingras AC; Institute of Biochemistry, ETH Zürich, Otto-Stern-Weg 3, 8093, Zürich, Switzerland.
  • Gratton JP; Montreal Clinical Research Institute (IRCM), Montréal, QC, H2W 1R7, Canada.
  • Côté JF; Montreal Clinical Research Institute (IRCM), Montréal, QC, H2W 1R7, Canada.
Nat Commun ; 11(1): 3586, 2020 07 17.
Article em En | MEDLINE | ID: mdl-32681075
ABSTRACT
Aberrant expression of receptor tyrosine kinase AXL is linked to metastasis. AXL can be activated by its ligand GAS6 or by other kinases, but the signaling pathways conferring its metastatic activity are unknown. Here, we define the AXL-regulated phosphoproteome in breast cancer cells. We reveal that AXL stimulates the phosphorylation of a network of focal adhesion (FA) proteins, culminating in faster FA disassembly. Mechanistically, AXL phosphorylates NEDD9, leading to its binding to CRKII which in turn associates with and orchestrates the phosphorylation of the pseudo-kinase PEAK1. We find that PEAK1 is in complex with the tyrosine kinase CSK to mediate the phosphorylation of PAXILLIN. Uncoupling of PEAK1 from AXL signaling decreases metastasis in vivo, but not tumor growth. Our results uncover a contribution of AXL signaling to FA dynamics, reveal a long sought-after mechanism underlying AXL metastatic activity, and identify PEAK1 as a therapeutic target in AXL positive tumors.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Tirosina Quinases / Movimento Celular / Proteínas Proto-Oncogênicas / Receptores Proteína Tirosina Quinases / Adesões Focais / Neoplasias Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Tirosina Quinases / Movimento Celular / Proteínas Proto-Oncogênicas / Receptores Proteína Tirosina Quinases / Adesões Focais / Neoplasias Idioma: En Ano de publicação: 2020 Tipo de documento: Article