Format

Send to

Choose Destination
Eur J Med Genet. 2015 Oct;58(10):509-25. doi: 10.1016/j.ejmg.2015.08.005. Epub 2015 Sep 2.

SHP2 sails from physiology to pathology.

Author information

1
Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France.
2
Endocrine, Bone Diseases, and Genetics Unit, Children's Hospital, University Hospital Center of Purpan Toulouse, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1043, Toulouse, France.
3
Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France. Electronic address: armelle.yart@inserm.fr.

Abstract

Over the two past decades, mutations of the PTPN11 gene, encoding the ubiquitous protein tyrosine phosphatase SHP2 (SH2 domain-containing tyrosine phosphatase 2), have been identified as the causal factor of several developmental diseases (Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML), and metachondromatosis), and malignancies (juvenile myelomonocytic leukemia). SHP2 plays essential physiological functions in organism development and homeostasis maintenance by regulating fundamental intracellular signaling pathways in response to a wide range of growth factors and hormones, notably the pleiotropic Ras/Mitogen-Activated Protein Kinase (MAPK) and the Phosphoinositide-3 Kinase (PI3K)/AKT cascades. Analysis of the biochemical impacts of PTPN11 mutations first identified both loss-of-function and gain-of-function mutations, as well as more subtle defects, highlighting the major pathophysiological consequences of SHP2 dysregulation. Then, functional genetic studies provided insights into the molecular dysregulations that link SHP2 mutants to the development of specific traits of the diseases, paving the way for the design of specific therapies for affected patients. In this review, we first provide an overview of SHP2's structure and regulation, then describe its molecular roles, notably its functions in modulating the Ras/MAPK and PI3K/AKT signaling pathways, and its physiological roles in organism development and homeostasis. In the second part, we describe the different PTPN11 mutation-associated pathologies and their clinical manifestations, with particular focus on the biochemical and signaling outcomes of NS and NS-ML-associated mutations, and on the recent advances regarding the pathophysiology of these diseases.

KEYWORDS:

Functional genetics; Noonan syndrome; Noonan syndrome with multiple lentigines; PTPN11; Shp2; Signaling

PMID:
26341048
DOI:
10.1016/j.ejmg.2015.08.005
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center