title: AMOTL1 Promotes Breast Cancer Progression and Is Antagonized by Merlin.
abstract: The Hippo signaling network is a key regulator of cell fate. In the recent years, it was shown that its implication in cancer goes well beyond the sole role of YAP transcriptional activity and its regulation by the canonical MST/LATS kinase cascade. Here we show that the motin family member AMOTL1 is an important effector of Hippo signaling in breast cancer. AMOTL1 connects Hippo signaling to tumor cell aggressiveness. We show that both canonical and noncanonical Hippo signaling modulates AMOTL1 levels. The tumor suppressor Merlin triggers AMOTL1 proteasomal degradation mediated by the NEDD family of ubiquitin ligases through direct interaction. In parallel, YAP stimulates AMOTL1 expression. The loss of Merlin expression and the induction of Yap activity that are frequently observed in breast cancers thus result in elevated AMOTL1 levels. AMOTL1 expression is sufficient to trigger tumor cell migration and stimulates proliferation by activating c-Src. In a large cohort of human breast tumors, we show that AMOTL1 protein levels are upregulated during cancer progression and that, importantly, the expression of AMOTL1 in lymph node metastasis appears predictive of the risk of relapse. Hence we uncover an important mechanism by which Hippo signaling promotes breast cancer progression by modulating the expression of AMOTL1.
authors.affiliation: Institut Curie, Paris, France; CNRS UMR144, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Couderc
authors.affiliation: Institut Curie, Paris, France; CNRS UMR144, Paris, France.
authors.forename: Alizée
authors.initials: A
authors.lastname: Boin
authors.affiliation: Institut Curie, Paris, France; CNRS UMR144, Paris, France; Department of Biopathology, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fuhrmann
authors.affiliation: Institut Curie, Paris, France; Department of Biopathology, Paris, France; INSERM U934, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Institut Curie, Paris, France; CNRS UMR144, Paris, France.
authors.forename: Vinay
authors.initials: V
authors.lastname: Mandati
authors.affiliation: Institut Curie, Paris, France; Stress and Cancer Laboratory, INSERM U830, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Kieffer
authors.affiliation: Institut Curie, Paris, France; Stress and Cancer Laboratory, INSERM U830, France.
authors.forename: Fatima
authors.initials: F
authors.lastname: Mechta-Grigoriou
authors.affiliation: Institut Curie, Paris, France; CNRS UMR144, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Del Maestro
authors.affiliation: Institut Curie, Paris, France; CNRS UMR144, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavrier
authors.affiliation: Institut Curie, Paris, France; Département de Recherche Translationnelle, Laboratoire d'Investigation Préclinique, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Vallerand
authors.affiliation: Institut Curie, Paris, France; INSERM U900, Paris, France; Mines ParisTech, Fontainebleau, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Brito
authors.affiliation: Institut Curie, Paris, France; Département de Recherche Translationnelle, Breast Cancer Biology Group, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Dubois
authors.affiliation: Institut Curie, Paris, France; RPPA Platform, Paris, France.
authors.forename: Leanne
authors.initials: L
authors.lastname: De Koning
authors.affiliation: INSERM U823, Institut Albert Bonniot, Grenoble, France; Université Joseph Fourier, Grenoble, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bouvard
authors.affiliation: Institut Curie, Paris, France; CNRS UMR144, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Louvard
authors.affiliation: Ecole Polytechnique, CNRS UMR7654 Palaiseau, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Gautreau
authors.affiliation: Institut Curie, Paris, France; CNRS UMR144, Paris, France. Electronic address: dominique.lallemand@inserm.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lallemand
mesh_terms: D000091082:Angiomotins; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C510063:AMOTL1 protein, human; D000091082:Angiomotins; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D025581:Neurofibromin 2; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D019061:src-Family Kinases