title: IQGAP1 regulates ERK1/2 and AKT signalling in the heart and sustains functional remodelling upon pressure overload.
abstract: OBJECTIVE
  The Raf-MEK1/2-ERK1/2 (ERK1/2-extracellular signal-regulated kinases 1/2) signalling cascade is crucial in triggering cardiac responses to different stress stimuli. Scaffold proteins are key elements in coordinating signalling molecules for their appropriate spatiotemporal activation. Here, we investigated the role of IQ motif-containing GTPase-activating protein 1 (IQGAP1), a scaffold for the ERK1/2 cascade, in heart function and remodelling in response to pressure overload.
  
  
  RESULTS
  IQGAP1-null mice have unaltered basal heart function. When subjected to pressure overload, IQGAP1-null mice initially develop a compensatory hypertrophy indistinguishable from that of wild-type (WT) mice. However, upon a prolonged stimulus, the hypertrophic response develops towards a thinning of left ventricular walls, chamber dilation, and a decrease in contractility, in an accelerated fashion compared with WT mice. This unfavourable cardiac remodelling is characterized by blunted reactivation of the foetal gene programme, impaired cardiomyocyte hypertrophy, and increased cardiomyocyte apoptosis. Analysis of signalling pathways revealed two temporally distinct waves of both ERK1/2 and AKT phosphorylation peaking, respectively, at 10 min and 4 days after aortic banding in WT hearts. IQGAP1-null mice show strongly impaired phosphorylation of MEK1/2-ERK1/2 and AKT following 4 days of pressure overload, but normal activation of these kinases after 10 min. Pull-down experiments indicated that IQGAP1 is able to bind the three components of the ERK cascade, namely c-Raf, MEK1/2, and ERK1/2, as well as AKT in the heart.
  
  
  CONCLUSIONS
  These data demonstrate, for the first time, a key role for the scaffold protein IQGAP1 in integrating hypertrophy and survival signals in the heart and regulating long-term left ventricle remodelling upon pressure overload.
authors.affiliation: Dipartimento di Genetica, Biologia e Biochimica, Molecular Biotechnology Center, Università di Torino, via Nizza 52, Turin, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Sbroggiò
authors.forename: Daniela
authors.initials: D
authors.lastname: Carnevale
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertero
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cifelli
authors.forename: Emanuele
authors.initials: E
authors.lastname: De Blasio
authors.forename: Giada
authors.initials: G
authors.lastname: Mascio
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Wadie F
authors.initials: WF
authors.lastname: Bahou
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.forename: Mara
authors.initials: M
authors.lastname: Brancaccio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
authors.forename: Guido
authors.initials: G
authors.lastname: Tarone
mesh_terms: D000818:Animals; D001011:Aorta / Q000503:physiopathology / Q000601:surgery; D017209:Apoptosis; D001794:Blood Pressure; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006973:Hypertension / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D008026:Ligation; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014463:Ultrasonography; D020257:Ventricular Remodeling; D020703:ras GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C101203:IQ motif containing GTPase activating protein 1; D020703:ras GTPase-Activating Proteins; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse