title: SHP-2 acts via ROCK to regulate the cardiac actin cytoskeleton.
abstract: Noonan syndrome is one of the most common causes of human congenital heart disease and is frequently associated with missense mutations in the protein phosphatase SHP-2. Interestingly, patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), juvenile myelomonocytic leukemia (JMML) and LEOPARD syndrome frequently carry a second, somatically introduced subset of missense mutations in SHP-2. To determine the cellular and molecular mechanisms by which SHP-2 regulates heart development and, thus, understand how Noonan-associated mutations affect cardiogenesis, we introduced SHP-2 encoding the most prevalent Noonan syndrome and JMML mutations into Xenopus embryos. Resulting embryos show a direct relationship between a Noonan SHP-2 mutation and its ability to cause cardiac defects in Xenopus; embryos expressing Noonan SHP-2 mutations exhibit morphologically abnormal hearts, whereas those expressing an SHP-2 JMML-associated mutation do not. Our studies indicate that the cardiac defects associated with the introduction of the Noonan-associated SHP-2 mutations are coupled with a delay or arrest of the cardiac cell cycle in M-phase and a failure of cardiomyocyte progenitors to incorporate into the developing heart. We show that these defects are a result of an underlying malformation in the formation and polarity of cardiac actin fibers and F-actin deposition. We show that these defects can be rescued in culture and in embryos through the inhibition of the Rho-associated, coiled-coil-containing protein kinase 1 (ROCK), thus demonstrating a direct relationship between SHP-2(N308D) and ROCK activation in the developing heart.
authors.affiliation: University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599-3280, USA.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Langdon
authors.forename: Panna
authors.initials: P
authors.lastname: Tandon
authors.forename: Erika
authors.initials: E
authors.lastname: Paden
authors.forename: Jennifer
authors.initials: J
authors.lastname: Duddy
authors.forename: Joan M
authors.initials: JM
authors.lastname: Taylor
authors.forename: Frank L
authors.initials: FL
authors.lastname: Conlon
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology; D006801:Humans; D020125:Mutation, Missense; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000648:ultrastructure; D009634:Noonan Syndrome / Q000201:enzymology / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis / Q000033:anatomy & histology / Q000196:embryology*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D054460:rho-Associated Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11