This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Princen, F. Articles by Feng, G.-S. Search for Related Content PubMed PubMed Citation Articles by Princen, F. Articles by Feng, G.-S.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, January 2009, p. 378-388, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01661-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Deletion of Shp2 Tyrosine Phosphatase in Muscle Leads to Dilated Cardiomyopathy, Insulin Resistance, and Premature Death

Frederic Princen,¹ Emilie Bard,¹ Farah Sheikh,² Sharon S. Zhang,¹ Jing Wang,¹ Wagner M. Zago,¹ Dongmei Wu,¹ Ramon Diaz Trelles,¹ Beatrice Bailly-Maitre,¹ C. Ronald Kahn,⁴ Yan Chen,⁵ John C. Reed,¹ Gary G. Tong,^1,3 Mark Mercola,¹ Ju Chen,² and Gen-Sheng Feng^1,6*

Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, California 92037,¹ Department of Medicine, University of California San Diego, La Jolla, California 92093,² Department of Neurosciences, University of California, San Diego, La Jolla, California 92093,³ Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215,⁴ Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai 200031, China,⁵ Institute for Biomedical Research, Xiamen University, Xiamen 361005, China⁶

Received 24 October 2008/ Accepted 27 October 2008

The intracellular signaling mechanisms underlying the pathogenesis of cardiac diseases are not fully understood. We report here that selective deletion of Shp2, an SH2-containing cytoplasmic tyrosine phosphatase, in striated muscle results in severe dilated cardiomyopathy in mice, leading to heart failure and premature mortality. Development of cardiomyopathy in this mouse model is coupled with insulin resistance, glucose intolerance, and impaired glucose uptake in striated muscle cells. Shp2 deficiency leads to upregulation of leukemia inhibitory factor-stimulated phosphatidylinositol 3-kinase/Akt, Erk5, and Stat3 pathways in cardiomyocytes. Insulin resistance and impaired glucose uptake in Shp2-deficient mice are at least in part due to impaired protein kinase C-/ and AMP-kinase activities in striated muscle. Thus, we have generated a mouse line modeling human patients suffering from cardiomyopathy and insulin resistance. This study reinforces a concept that a compound disease with multiple cardiovascular and metabolic disturbances can be caused by a defect in a single molecule such as Shp2, which modulates multiple signaling pathways initiated by cytokines and hormones.

---

* Corresponding author. Mailing address: Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 795-5265. Fax: (858) 713-6274. E-mail: gfeng{at}burnham.org

Published ahead of print on 10 November 2008.

---

Molecular and Cellular Biology, January 2009, p. 378-388, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01661-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• McPherson, V. A., Sharma, N., Everingham, S., Smith, J., Zhu, H. H., Feng, G.-S., Craig, A. W. B. (2009). SH2 Domain-Containing Phosphatase-2 Protein-Tyrosine Phosphatase Promotes Fc{epsilon}RI-Induced Activation of Fyn and Erk Pathways Leading to TNF{alpha} Release from Bone Marrow-Derived Mast Cells. J. Immunol. 183: 4940-4947 [Abstract] [Full Text]