Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Apr;112(4):403-421.
doi: 10.1007/s00223-022-01042-3. Epub 2022 Nov 24.

From Stem to Sternum: The Role of Shp2 in the Skeleton

Nathaniel R Jensen #  1 , Ryan R Kelly #  2   3 , Kirsten D Kelly  2 , Stephanie K Khoo  2 , Sara J Sidles  2   3 , Amanda C LaRue  4   5
Affiliations
Review

From Stem to Sternum: The Role of Shp2 in the Skeleton

Nathaniel R Jensen et al. Calcif Tissue Int. 2023 Apr.

Abstract

Src homology-2 domain-containing phosphatase 2 (SHP2) is a ubiquitously expressed phosphatase that is vital for skeletal development and maintenance of chondrocytes, osteoblasts, and osteoclasts. Study of SHP2 function in small animal models has led to insights in phenotypes observed in SHP2-mutant human disease, such as Noonan syndrome. In recent years, allosteric SHP2 inhibitors have been developed to specifically target the protein in neoplastic processes. These inhibitors are highly specific and have great potential for disease modulation in cancer and other pathologies, including bone disorders. In this review, we discuss the importance of SHP2 and related signaling pathways (e.g., Ras/MEK/ERK, JAK/STAT, PI3K/Akt) in skeletal development. We review rodent models of pathologic processes caused by germline mutations that activate SHP2 enzymatic activity, with a focus on the skeletal phenotype seen in these patients. Finally, we discuss SHP2 inhibitors in development and their potential for disease modulation in these genetic diseases, particularly as it relates to the skeleton.

Keywords: Bone; Development; SHP099; SHP2; Skeleton.

PubMed Disclaimer

References

    1. Ahmad S, Banville D, Zhao Z, Fischer EH, Shen SH (1993) A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains. Proc Natl Acad Sci U S A 90:2197–2201. https://doi.org/10.1073/pnas.90.6.2197 - DOI - PubMed - PMC
    1. 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. https://doi.org/10.1016/S0968-0004(03)00091-4 - DOI - PubMed
    1. Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE (1998) Crystal structure of the tyrosine phosphatase SHP-2. Cell 92:441–450. https://doi.org/10.1016/s0092-8674(00)80938-1 - DOI - PubMed
    1. Yu Z-H, Xu J, Walls CD, Chen L, Zhang S, Zhang R et al (2013) Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations. J Biol Chem 288:10472–10482. https://doi.org/10.1074/jbc.M113.450023 - DOI - PubMed - PMC
    1. Ran H, Tsutsumi R, Araki T, Neel BG (2016) Sticking it to cancer with molecular glue for SHP2. Cancer Cell 30:194–196. https://doi.org/10.1016/j.ccell.2016.07.010 - DOI - PubMed - PMC

Publication types

Substances

LinkOut - more resources