title: Insulin-induced cell division is controlled by the adaptor Grb14 in a Chfr-dependent manner.
abstract: Beyond its key role in the control of energy metabolism, insulin is also an important regulator of cell division and neoplasia. However, the molecular events involved in insulin-driven cell proliferation are not fully elucidated. Here, we show that the ubiquitin ligase Chfr, a checkpoint protein involved in G2/M transition, is a new effector involved in the control of insulin-induced cell proliferation. Chfr is identified as a partner of the molecular adapter Grb14, an inhibitor of insulin signalling. Using mammalian cell lines and the Xenopus oocyte as a model of G2/M transition, we demonstrate that Chfr potentiates the inhibitory effect of Grb14 on insulin-induced cell division. Insulin stimulates Chfr binding to the T220 residue of Grb14. Both Chfr binding site and Grb14 C-ter BPS-SH2 domain, mediating IR binding and inhibition, are required to prevent insulin-induced cell division. Targeted mutagenesis revealed that Chfr ligase activity and phosphorylation of its T39 residue, a target of Akt, are required to potentiate Grb14 inhibitory activity. In the presence of insulin, the binding of Chfr to Grb14 activates its ligase activity, leading to Aurora A and Polo-like kinase degradation and blocking cell division. Collectively, our results show that Chfr and Grb14 collaborate in a negative feedback loop controlling insulin-stimulated cell division.
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité; 24, Rue du Faubourg Saint Jacques, Paris 75014, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Perdereau
authors.affiliation: Laboratoire de Régulation des Signaux de Division, Université de Lille 1, UE 4479, IFR 147, Villeneuve d'Ascq 59655, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Cailliau
authors.affiliation: Laboratoire de Régulation des Signaux de Division, Université de Lille 1, UE 4479, IFR 147, Villeneuve d'Ascq 59655, France.
authors.forename: Edith
authors.initials: E
authors.lastname: Browaeys-Poly
authors.affiliation: Laboratoire de Régulation des Signaux de Division, Université de Lille 1, UE 4479, IFR 147, Villeneuve d'Ascq 59655, France.
authors.forename: Arlette
authors.initials: A
authors.lastname: Lescuyer
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité; 24, Rue du Faubourg Saint Jacques, Paris 75014, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Carré
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité; 24, Rue du Faubourg Saint Jacques, Paris 75014, France.
authors.forename: Fadila
authors.initials: F
authors.lastname: Benhamed
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité; 24, Rue du Faubourg Saint Jacques, Paris 75014, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Goenaga
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité; 24, Rue du Faubourg Saint Jacques, Paris 75014, France. Electronic address: anne-francoise.burnol@inserm.fr.
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Burnol
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D055786:Gene Knockout Techniques; D007328:Insulin / Q000378:metabolism*; D016296:Mutagenesis; D000075223:Poly-ADP-Ribose Binding Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus; D000097869:Polo-Like Kinase 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D007328:Insulin; D000075223:Poly-ADP-Ribose Binding Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D044767:Ubiquitin-Protein Ligases; D000097869:Polo-Like Kinase 1; C490976:Grb14 protein, rat; C000603665:Chfr protein, rat
keywords: Cancer; Cell proliferation; Grb14; Insulin signalling