title: PINCH proteins regulate cardiac contractility by modulating integrin-linked kinase-protein kinase B signaling.
abstract: Integrin-linked kinase (ILK) is an essential component of the cardiac mechanical stretch sensor and is bound in a protein complex with parvin and PINCH proteins, the so-called ILK-PINCH-parvin (IPP) complex. We have recently shown that inactivation of ILK or β-parvin activity leads to heart failure in zebrafish via reduced protein kinase B (PKB/Akt) activation. Here, we show that PINCH proteins localize at sarcomeric Z disks and costameres in the zebrafish heart and skeletal muscle. To investigate the in vivo role of PINCH proteins for IPP complex stability and PKB signaling within the vertebrate heart, we inactivated PINCH1 and PINCH2 in zebrafish. Inactivation of either PINCH isoform independently leads to instability of ILK, loss of stretch-responsive anf and vegf expression, and progressive heart failure. The predominant cause of heart failure in PINCH morphants seems to be loss of PKB activity, since PKB phosphorylation at serine 473 is significantly reduced in PINCH-deficient hearts and overexpression of constitutively active PKB reconstitutes cardiac function in PINCH morphants. These findings highlight the essential function of PINCH proteins in controlling cardiac contractility by granting IPP/PKB-mediated signaling.
authors.affiliation: Department of Medicine III, University of Heidelberg, Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.forename: Inken G
authors.initials: IG
authors.lastname: Huttner
authors.forename: Farbod
authors.initials: F
authors.lastname: Sedaghat-Hamedani
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.forename: Tillman
authors.initials: T
authors.lastname: Dahme
authors.forename: Karen S
authors.initials: KS
authors.lastname: Frese
authors.forename: Britta
authors.initials: B
authors.lastname: Vogel
authors.forename: Doreen
authors.initials: D
authors.lastname: Köhler
authors.forename: Wanda
authors.initials: W
authors.lastname: Kloos
authors.forename: Jessica
authors.initials: J
authors.lastname: Rudloff
authors.forename: Sabine
authors.initials: S
authors.lastname: Marquart
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
mesh_terms: D000818:Animals; D006333:Heart Failure / Q000209:etiology; D009124:Muscle Proteins / Q000502:physiology*; D018482:Muscle, Skeletal; D009200:Myocardial Contraction; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012518:Sarcomeres / Q000737:chemistry; D015398:Signal Transduction / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000502:physiology*; D000099200:Scaffold Protein ILK
chemical_list: D009124:Muscle Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D029961:Zebrafish Proteins; D000099200:Scaffold Protein ILK; C562196:lims1 protein, zebrafish; C562197:lims2 protein, zebrafish