• David Aphkhazava David Agmashenebeli University of Georgia image/svg+xml
  • Tamar Tuphinashvili David Agmashenebeli University of Georgia image/svg+xml
  • Nodar Sulashvili David Agmashenebeli University of Georgia image/svg+xml
  • Maia Nozadze U.S. Army Medical Research Directorate-Georgia



tyrosine phosphatase Ptpn11 (Shp2), Pax 7, Myo D, Myf 5, Myo G, muscle cell, development, stem cells


SHP-2 (encoded by PTPN11) is a ubiquitously expressed protein tyrosine phosphatase required for signal transduction by multiple different cell surface receptors. Humans with carry germline SHP-2 mutations develop Noonan syndrome or LEOPARD syndrome, which are characterized by cardiovascular, neurological and skeletal abnormalities.Shp2 is an important signaling agent for growth factors and cytokines. To investigate the Ptpn11 in postnatal myogenesis of mice  we analyzed using immunohistochemistry stem cell markers: Pax 7, Myo D, Myf 5 and Myo G in muscle cells isolated from wild type and Shp2 knockout mice. We used a conditional SHP-2 mouse mutant in which loss of expression of SHP-2 was induced in multiple tissues in response to drug administration. Our findings indicate that all these markers gradually decreased from birth to day 14 in mouse muscle cells. Here we show that Shp2, an intracellular tyrosine phosphatase with two SH2 domains, plays a critical role in mouse muscle development after birth. Our data demonstrate a molecular difference in the control and Sh2 knockout  postnatal myogenic stem cells, and assign to Ptpn11 signaling a key function in satellite cell activity. These findings illustrate an essential role for Shp-2 in muscle growth and remodeling in adults, and reveal some of the cellular and molecular mechanisms involved. The model is predicted to be of further use in understanding how Shp-2 regulates muscle morphogenesis, which could lead to the development of novel therapies for the treatment of malformations in human patients with SHP-2 mutations.


Download data is not yet available.

Author Biographies

David Aphkhazava, David Agmashenebeli University of Georgia

PhD, Professor

Tamar Tuphinashvili, David Agmashenebeli University of Georgia

PhD, Professor

Nodar Sulashvili, David Agmashenebeli University of Georgia

MD, PhD, Professor


Butterworth S, Overduin M, Barr AJ. Targeting protein tyrosine phosphatase SHP2 for therapeutic intervention. Future Med Chem. 2014;6(12):1423-37. doi: 10.4155/fmc.14.88.

Chong, Z. Z. and Maiese, K. (2007). The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversified control of cell growth, inflammation, and injury. Histol. Histopathol. 22, 1251-1267.

Saint-Laurent C, Mazeyrie L, Tajan M et al., The Tyrosine Phosphatase SHP2: A New Target for Insulin Resistance? Biomedicines. 2022 Sep; 10(9): 2139. Published online 2022 Aug 31. doi: 10.3390/biomedicines10092139.

Matozaki, T., Murata, Y., Saito, Y., Okazawa, H. and Ohnishi, H. (2009). Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer Sci. 100, 1786-1793.

Asmamaw M. D., Shi X.-J., Zhang L.-R., Liu H.-M., Zhang L.-R. (2022). A comprehensive review of SHP2 and its role in cancer. Cell. Oncol. 2022, 729–753.

Grossmann K. S., Rosário M., Birchmeier C., Birchmeier W. (2010). The tyrosine phosphatase Shp2 in development and cancer. Adv. Cancer Res. 106, 53–89. Schaeper U, et al. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. J Cell Biol. 2000;149:1419–1432.

8.Liu M., Gao S., ElhassanR.M., X. Hou, and H. Fang Strategies to overcome drug resistance using SHP2 inhibitors. Acta Pharm Sin B. 2021 Dec; 11(12): 3908–3924. Published online 2021 Mar 28.

Yu ZH, Zhang Ry, Walls CD, et al.,. Molecular Basis of Gain-of-Function LEOPARD Syndrome-Associated SHP2 Mutations. Biochemistry. 2014 Jul 1; 53(25): 4136–4151. Published online 2014 Jun 8.

Griger J., Schneider R., Lahmann I., et al., 1 Loss of Ptpn11 (Shp2) drives satellite cells into quiescence. Elife. 2017 May 2;6:e21552.

Neel BG, Gu H, Pao L (2003) The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci 28:284–293.

Von Maltzahn J, Jones AE, Parks RJ, Rudnicki MA. 2013. Pax7 is critical for the normal function of satellite cells in adult skeletal muscle. Proc Natl Acad Sci USA. 110 (41):16474.

Kuang S, Charge SB, Seale P, Huh M, Rudnicki MA. Distinct roles for Pax7 and Pax3 in adult regenerative myogenesis. J Cell Biol. 2006;172:103–13.

Megeney L. & Rudnicki, M. A. Determination versus differentation and the MyoD family of transcription factors. Biochem. Cell Biol. 73, 723–732 (2005).

Perry R. L. & Rudnicki, M. A. Molecular mechanisms regulating myogenic determination and differentiation. Front. Biosci. 5, D570–D767 (2000).

Hughes S. M. et al. Selective accumulation of myoD and myogenin mRNAs in fast and slow adult skeletal muscle is controlled by innervation and hormones. Development 118, 1137–1147 (2004).

Maves L. et al. Pbx homeodomain proteins direct MyoD activity to promote fast-muscle differentiation. Development 134, 3371–3382 (2007).

Ganassi M, Badodi S, Wanders K, et al., Myogenin is an essential regulator of adult myofibre growth and muscle stem cell homeostasis. eLife. 2020; 9: e60445. doi: 10.7554/eLife.60445.

Arnold HH, Braun T. Genetics of muscle determination and development. Curr Top Dev Biol 2000; 48: 129– 164.

Kaul A, Koster M, Neuhaus H et al. Myf-5 revisited: Loss of early myotome formation does not lead to a rib phenotype in homozygous Myf-5 mutant mice. Cell 2000; 102: 17– 19.

Hasty P, Bradley A, Morris JH, Edmondson DG, Venuti JM, Olson EN, Klein WH (2008). Muscle deficiency and neonathal death in mice with targeted mutation in the Myogenin locus. Nature 364:501-506.

Nabeshima Y, Hanaoka K, Hayasaka M, Esumi E, Li S, Nonaka I., Nabeshima Y (2014). Gene disruption results in perinatal lethality because of severe muscle defects. Nature 364:532-535.

Hernández-Hernández JM, García-González EG, Brun CE, Rudnicki MA. 2017. The myogenic regulatory factors, determinants of muscle development, cell identity and regeneration. Semin Cell Dev Biol. 72:10–18.

Bröhl D, Vasyutina E, Czajkowski MT, Griger J, Rassek C, Rahn HP, Purfürst B, Wende H, Birchmeier C. Colonization of the satellite cell niche by skeletal muscle progenitor cells depends on notch signals. Developmental Cell. 2012; 23:469–481. Gromova A , Tierney MT, Sacco A FACS-based Satellite Cell Isolation From Mouse Hind Limb Muscles Bio Protoc, 2015 Aug 20;5(16):e1558.




How to Cite