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Development 2012 Mar 01;1395:948-57. doi: 10.1242/dev.067579.
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SHP-2 acts via ROCK to regulate the cardiac actin cytoskeleton.

Langdon Y , Tandon P , Paden E , Duddy J , Taylor JM , Conlon FL .

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.

PubMed ID: 22278918
PMC ID: PMC3274356
Article link: Development
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: actc1 actl6a fbn1 fbn2 h3-3a myh4 myh6 nkx2-5 nr0b2 ptpn11 ptpru pxn rho rock1 rock2 runx1 tbx20 tbx5 tnnt2 tpm1
Antibodies: Fbn2 Ab1 H3f3a Ab3 Myh6 Ab2 Tbx5 Ab1 Tnnt2 Ab1 Tpm1 Ab1

Disease Ontology terms: juvenile myelomonocytic leukemia [+]
Phenotypes: Xla Wt + ptpn11{D61G} (Fig. S1 C) [+]

Article Images: [+] show captions
References [+] :
Ahuja, Re-expression of proteins involved in cytokinesis during cardiac hypertrophy. 2007, Pubmed