Review article
PTPN11-Associated Mutations in the Heart: Has LEOPARD Changed Its RASpots?

https://doi.org/10.1016/j.tcm.2012.03.006Get rights and content

In this review, we focus on elucidating the cardiac function of germline mutations in the PTPN11 gene, encoding the Src homology-2 (SH2) domain–containing protein tyrosine phosphatase SHP2. PTPN11 mutations cause LEOPARD syndrome (LS) and Noonan syndrome (NS), two disorders that are part of a newly classified family of autosomal dominant syndromes termed “RASopathies,” which are caused by germline mutations in components of the RAS/RAF/MEK/ERK mitogen activating protein kinase pathway. LS and NS mutants have opposing biochemical properties, and yet, in patients, these mutations produce similar cardiac abnormalities. Precisely how LS and NS mutations lead to such similar disease etiology remains largely unknown. Recent complementary in vitro, ex vivo, and in vivo analyses reveal new insights into the functions of SHP2 in normal and pathological cardiac development. These findings also reveal the need for individualized therapeutic approaches in the treatment of patients with LS and NS and, more broadly, patients with the other “RASopathy” gene mutations as well.

Introduction

Congenital heart disorders (CHDs) are the most common type of birth defect (∼1/100 live births) and the major cause of birth-related deaths (Weismann and Gelb 2007). Abnormalities in signaling molecules and/or pathways are implicated in CHD pathogenesis; however, underlying mechanisms remain poorly understood and/or unknown. Recently, a new family of autosomal dominant syndromes was recognized, termed “RASopathies” (Figure 1). These disorders, which include LEOPARD syndrome (LS) (OMIM: 151100) and Noonan syndrome (NS) (OMIM: 163950), are caused by germline mutations in components of the RAS/RAF/MEK/ERK mitogen activating protein kinase (MAPK) pathway (Tidyman and Rauen 2009), which is required for normal cell growth, differentiation, and survival. Aberrant regulation of this pathway has profound effects, particularly on cardiac development, resulting in various abnormalities, including valvuloseptal defects and/or hypertrophic cardiomyopathy (HCM). With perturbations of the MAPK signaling pathway established as central to RASopathy disorders, several candidate genes along this canonical pathway have been identified in humans with RASopathy disease phenotypes, including mutations in KRAS, NRAS, SOS1, RAF1, BRAF, MEK1, MEK2, SHOC2, and CBL (Carta et al., 2006, Cirstea et al., 2010, Cordeddu et al., 2009, Dentici et al., 2009, Martinelli et al., 2010, Niihori et al., 2006, Pandit et al., 2007, Razzaque et al., 2007, Roberts et al., 2007, Schubbert et al., 2006, Tartaglia et al., 2007) (Figure 1). The gene most commonly mutated in NS and LS is PTPN11 (Figure 1) (Tartaglia et al. 2001).

Section snippets

PTPN11: Structure and Function

PTPN11 encodes the Src homology-2 (SH2) domain–containing nontransmembrane protein tyrosine phosphatase (PTP) SHP2. SHP2 is a ubiquitously expressed protein that contains two SH2 domains, a central PTP catalytic domain and a C-terminal tail with two tyrosine phosphorylation sites and a proline-rich motif. Resolution of the crystal structure, along with biochemical validation, has elucidated its mechanism of regulation, whereby in the inactive state, the backside loop of the N-SH2 domain folds

PTPN11 Mutations in Human Disease

SHP2 mutants have functional significance and, therefore, biological consequences. Heterozygous missense mutations in PTPN11 are observed in up to 90% of LS cases. LS, a rare autosomal dominant disorder, is an acronym for its presenting features of multiple lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness (Digilio et al., 2002, Legius et al., 2002) and is also referred to as Noonan

NS and LS: Differential Mechanisms of PTPN11 Regulation

Because NS and LS share such similar phenotypic characteristics in patients, they were considered to have similar disease pathogenesis. Interestingly, the point mutations identified in PTPN11 that were associated with NS were distinct from those associated with LS (Table 2). Indeed, the biochemical properties between the PTPN11 NS- and LS-specific point mutations are quite different (Hanna et al., 2006, Kontaridis et al., 2006, Tartaglia et al., 2006). Most NS mutations reside within the N-SH2

Modeling LS-Associated Cardiac Hypertrophy

Interestingly, initial in vivo studies reported conflicting results on the PTP function of the LS mutations in PTPN11. In contrast to the in vitro studies that provocatively suggested that LS mutations were LOF (Hanna et al., 2006, Kontaridis et al., 2006, Tartaglia et al., 2006), expression of the LS mutants Y279C or T468M in Drosophila resulted in ectopic wing veins and a rough eye phenotype, characteristics of increased ERK/MAPK activity in these tissues. In addition, genetic analysis of

Modeling NS-Associated Cardiac Hypertrophy

Biochemical, cell biological, and genetic evidence indicate that PTPN11 mutations associated with NS are hypermorphs that can enhance ERK/MAPK pathway activation (Keilhack et al. 2005). However, differing NS PTPN11 mutations appear to result in uniquely differing cardiac phenotypes (Araki et al., 2004, Araki et al., 2009, Krenz et al., 2008). For example, approximately 50% of the knockin mice for the Ptpn11 D61G NS exhibit valvuloseptal defects similar to those observed in NS patients but with

RASopathies: Future Therapeutic Intervention for NS and LS

Collectively, the results of these studies raise awareness for the need for treatment of diseases and disorders based on biochemical, rather than phenotypic, presentation. This provides further impetus to proceed with efforts to identify the other disease genes underlying these disorders and to generate animal models as well as human cell model systems. For example, the continued development of iPSC technology might enable a deeper understanding of the molecular mechanisms underlying human

Acknowledgments

This work was supported by National Institutes of Health grant HL088514, the Milton Fund, and the Beth Israel Deaconess Medical Center Division of Cardiology (to M.I.K.).

References (85)

  • R.A. Klinghoffer et al.

    Identification of a putative Syp substrate, the PDGFβ receptor

    J Biol Chem

    (1995)
  • M.I. Kontaridis et al.

    PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects

    J Biol Chem

    (2006)
  • G. Limongelli et al.

    Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome

    Am J Cardiol

    (2007)
  • B. Marino et al.

    Congenital heart diseases in children with Noonan syndrome: An expanded cardiac spectrum with high prevalence of atrioventricular canal

    J Pediatr

    (1999)
  • S. Martinelli et al.

    Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype

    Am J Hum Genet

    (2010)
  • B.G. Neel et al.

    The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling

    Trends Biochem Sci

    (2003)
  • W.H. Shen et al.

    Cardiac restricted overexpression of kinase-dead mammalian target of rapamycin (mTOR) mutant impairs the mTOR-mediated signaling and cardiac function

    J Biol Chem

    (2008)
  • R.A. Stewart et al.

    Phosphatase-dependent and -independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis

    Dev Cell

    (2010)
  • M. Tartaglia et al.

    PTPN11 mutations in Noonan syndrome: Molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity

    Am J Hum Genet

    (2002)
  • M. Tartaglia et al.

    Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease

    Am J Hum Genet

    (2006)
  • W.E. Tidyman et al.

    The RASopathies: Developmental syndromes of Ras/MAPK pathway dysregulation

    Curr Opin Genet Dev

    (2009)
  • N.K. Tonks et al.

    Combinatorial control of the specificity of protein tyrosine phosphatases

    Curr Opin Cell Biol

    (2001)
  • Y. Wang et al.

    Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells

    J Biol Chem

    (1998)
  • S.Q. Zhang et al.

    Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment

    Mol Cell

    (2004)
  • Y.M. Agazie et al.

    Molecular mechanism for a role of SHP2 in epidermal growth factor receptor signaling

    Mol Cell Biol

    (2003)
  • J. Alexandre et al.

    Rapamycin and CCI-779

    Bull Cancer

    (1999)
  • T. Araki et al.

    Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation

    Proc Natl Acad Sci U S A

    (2009)
  • T. Araki et al.

    Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation

    Nat Med

    (2004)
  • A.M. Bennett et al.

    Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor β to Ras

    Proc Natl Acad Sci U S A

    (1994)
  • M.O. Boluyt et al.

    Rapamycin inhibits alpha 1-adrenergic receptor-stimulated cardiac myocyte hypertrophy but not activation of hypertrophy-associated genes: Evidence for involvement of p70 S6 kinase

    Circ Res

    (1997)
  • O.F. Bueno et al.

    The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice

    EMBO J

    (2000)
  • X. Carvajal-Vergara et al.

    Patient-specific induced pluripotent stem-cell–derived models of LEOPARD syndrome

    Nature

    (2011)
  • P.C. Chen et al.

    Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome-associated Sos1 mutation

    J Clin Invest

    (2010)
  • I.C. Cirstea et al.

    A restricted spectrum of NRAS mutations causes Noonan syndrome

    Nat Genet

    (2010)
  • V. Cordeddu et al.

    Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair

    Nat Genet

    (2009)
  • E. Darian et al.

    Structural mechanism associated with domain opening in gain-of-function mutations in SHP2 phosphatase

    Proteins

    (2011)
  • M.L. Dentici et al.

    Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype-phenotype correlations

    Eur J Hum Genet

    (2009)
  • T. Edouard et al.

    Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling

    Mol Cell Biol

    (2010)
  • Y. Fujioka et al.

    A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion

    Mol Cell Biol

    (1996)
  • X.M. Gao et al.

    Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis

    J Hypertens

    (2006)
  • R.J. Gorlin et al.

    The Leopard (multiple lentigines) syndrome revisited

    Birth Defects Orig Artic Ser

    (1971)
  • E.B. Haura et al.

    A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer

    Clin Cancer Res

    (2010)
  • Cited by (0)

    View full text