PMID- 26341048 OWN - NLM STAT- MEDLINE DCOM- 20160819 LR - 20151103 IS - 1878-0849 (Electronic) IS - 1769-7212 (Linking) VI - 58 IP - 10 DP - 2015 Oct TI - SHP2 sails from physiology to pathology. PG - 509-25 LID - S1769-7212(15)30012-4 [pii] LID - 10.1016/j.ejmg.2015.08.005 [doi] AB - 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. CI - Copyright (c) 2015 Elsevier Masson SAS. All rights reserved. FAU - Tajan, Mylene AU - Tajan M AD - Institut National de la Sante et de la Recherche Medicale (INSERM), U1048, Toulouse, France; Universite de Toulouse, Universite Paul Sabatier, Institut des Maladies Metaboliques et Cardiovasculaires, Toulouse, France. FAU - de Rocca Serra, Audrey AU - de Rocca Serra A AD - Institut National de la Sante et de la Recherche Medicale (INSERM), U1048, Toulouse, France; Universite de Toulouse, Universite Paul Sabatier, Institut des Maladies Metaboliques et Cardiovasculaires, Toulouse, France. FAU - Valet, Philippe AU - Valet P AD - Institut National de la Sante et de la Recherche Medicale (INSERM), U1048, Toulouse, France; Universite de Toulouse, Universite Paul Sabatier, Institut des Maladies Metaboliques et Cardiovasculaires, Toulouse, France. FAU - Edouard, Thomas AU - Edouard T AD - Endocrine, Bone Diseases, and Genetics Unit, Children's Hospital, University Hospital Center of Purpan Toulouse, France; Institut National de la Sante et de la Recherche Medicale (INSERM), U1043, Toulouse, France. FAU - Yart, Armelle AU - Yart A AD - Institut National de la Sante et de la Recherche Medicale (INSERM), U1048, Toulouse, France; Universite de Toulouse, Universite Paul Sabatier, Institut des Maladies Metaboliques et Cardiovasculaires, Toulouse, France. Electronic address: armelle.yart@inserm.fr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20150902 PL - Netherlands TA - Eur J Med Genet JT - European journal of medical genetics JID - 101247089 RN - EC 3.1.3.48 (PTPN11 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) SB - IM MH - Amino Acid Sequence MH - Animals MH - Humans MH - Molecular Sequence Data MH - Mutation MH - Noonan Syndrome/*genetics/metabolism/pathology MH - Protein Tyrosine Phosphatase, Non-Receptor Type 11/chemistry/*genetics/metabolism MH - Signal Transduction OTO - NOTNLM OT - Functional genetics OT - Noonan syndrome OT - Noonan syndrome with multiple lentigines OT - PTPN11 OT - Shp2 OT - Signaling EDAT- 2015/09/06 06:00 MHDA- 2016/08/20 06:00 CRDT- 2015/09/06 06:00 PHST- 2015/04/28 00:00 [received] PHST- 2015/07/24 00:00 [revised] PHST- 2015/08/30 00:00 [accepted] PHST- 2015/09/06 06:00 [entrez] PHST- 2015/09/06 06:00 [pubmed] PHST- 2016/08/20 06:00 [medline] AID - S1769-7212(15)30012-4 [pii] AID - 10.1016/j.ejmg.2015.08.005 [doi] PST - ppublish SO - Eur J Med Genet. 2015 Oct;58(10):509-25. doi: 10.1016/j.ejmg.2015.08.005. Epub 2015 Sep 2.