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Protein Tyrosine Phosphatase Control of Metabolism pp 147–167Cite as

Role of the SHP2 Protein Tyrosine Phosphatase in Cardiac Metabolism

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Abstract

The heart relies heavily on oxidation and requires an integrally responsive metabolic function to maintain cardiac homeostasis. There is increasing evidence that it is this loss of metabolic flexibility that ultimately leads to cardiac dysfunction in disease conditions such as diabetes, ischemic heart disease, hypertrophic cardiomyopathy (HCM), and heart failure.

The SH2 domain-containing protein tyrosine phosphatase (PTP), Src homology protein 2 (SHP2), encoded by the PTPN11 gene, is the first PTP to be directly implicated in cardiac disease (Nat Genet, 29(4):465–468, 2001; J Med Genet 39(8):571–574, 2002; J Med Genet 40(9):704–708, 2003) and is the first identified PTP found to have a critical role in adult cardiac function (Circulation 117(11):1423–1435, 2008; Mol Cell Biol 29(2):378–388, 2009). Indeed, differing mutations within SHP2 elicit distinct biochemical properties of the enzyme, each manifesting in a unique panoply of cardiac defects, including HCM.

Given the already identified key role for SHP2 in the heart, it is likely that SHP2 plays a significant role in cardiac metabolism as well. However, while the critical signaling pathways necessary for metabolic function in the heart overlap significantly with those known to be controlled by SHP2, a direct role for SHP2 in cardiac metabolism has not yet been elucidated. Here, we will discuss what is known about the functional role for SHP2 in the heart, how mutations in SHP2 can affect cardiac disease progression, and what direct or indirect mechanisms may exist for SHP2 regulation of cardiac metabolism.

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Abbreviations

AMPK:

Adenosine monophosphate-activated protein kinase

ATP:

Adenosine triphosphate

CHDs:

Congenital heart defects

CICR:

Calcium-induced calcium release

CM:

Cardiomyocyte

Db/Db:

Diabetes/diabetes

DCM:

Dilated cardiomyopathy

EGFR:

Epidermal growth factor receptor

ERK:

Extracellular regulated kinase

ET-1:

Endothelin-1

ETC:

Electron transport chain

Ex3−/− :

Exon 3 deleted

FA:

Free fatty acids

FAK:

Focal adhesion kinase

FOXO:

Forkhead box transcription factors

FRS-2:

Fibroblast growth factor receptor substrate-2

GAB-1:

GRB2 associated binder-1

GLUT-1:

Glucose transporter type-1

GLUT-4:

Glucose transporter type-4

GOF:

Gain-of-function

GPCR:

G-protein coupled receptor

GSK3β:

Glycogen synthase kinase 3β

HB-EGF:

Heparin binding-epidermal growth factor

HCM:

Hypertrophic cardiomyopathy

HF:

Heart failure

IGF:

Insulin-like growth factor

IGFR:

Insulin-like growth factor receptor

IR:

Insulin receptor

IRS-1:

Insulin receptor substrate-1

JAK:

Janus kinases

LS:

Leopard syndrome

MAPK:

Mitogen-activated protein kinase

MEFs:

Mouse embryonic fibroblasts

MKK6:

Mitogen-activated protein kinase kinase 6

MMPs:

Metalloproteases

mTOR:

Mammalian target of Rapamycin

NADH:

Nicotinamide adenine dinucleotide

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-kB:

Nuclear factor B

NOS:

Nitric oxide synthase

NRVMs:

Neonatal rat ventricular myocytes

NS:

Noonan syndrome

Ob/Ob:

Obesity/obesity

OxPhos:

Oxidative phosphorylation

PDGF:

Platelet-derived growth factor

PI3K:

Phosphatidylinositol 3-kinase

PKC:

Protein kinase C

PTEN:

Phosphatase and tensin homolog deleted on chromosome ten

PTP:

Protein tyrosine phosphatase

PTPN11:

Protein tyrosine phosphatase non-receptor type-11

pY:

Phosphotyrosyl peptide

RhoA:

Ras homolog gene family, member A

ROS:

Reactive oxygen species

RTKs:

Receptor tyrosine kinases

SFK:

SRC family kinase

SH2:

Src homology 2

SHP2:

Src homology protein 2

STAT:

Signal transducer activator of transcription

T-tubule:

Transverse tubule

UT-II:

Urotensin-II

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Authors and Affiliations

  1. Department of Medicine, Division of Cardiology, and Department of Biological Chemistry and Molecular Pharmacology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA

    Maria I. Kontaridis Ph.D.

  2. Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA

    Eleni V. Geladari M.D. & Charalampia V. Geladari M.D.

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  1. Maria I. Kontaridis Ph.D.
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  2. Eleni V. Geladari M.D.
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  3. Charalampia V. Geladari M.D.
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Correspondence to Maria I. Kontaridis Ph.D. .

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  1. Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Kendra K. Bence

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Kontaridis, M.I., Geladari, E.V., Geladari, C.V. (2013). Role of the SHP2 Protein Tyrosine Phosphatase in Cardiac Metabolism. In: Bence, K. (eds) Protein Tyrosine Phosphatase Control of Metabolism. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7855-3_8

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