PMID- 31562133 OWN - NLM STAT- MEDLINE DCOM- 20200324 LR - 20210202 IS - 1528-0020 (Electronic) IS - 0006-4971 (Linking) VI - 134 IP - 25 DP - 2019 Dec 19 TI - Catalytic dysregulation of SHP2 leading to Noonan syndromes affects platelet signaling and functions. PG - 2304-2317 LID - 10.1182/blood.2019001543 [doi] AB - Src homology 2 domain-containing phosphatase 2 (SHP2), encoded by the PTPN11 gene, is a ubiquitous protein tyrosine phosphatase that is a critical regulator of signal transduction. Germ line mutations in the PTPN11 gene responsible for catalytic gain or loss of function of SHP2 cause 2 disorders with multiple organ defects: Noonan syndrome (NS) and NS with multiple lentigines (NSML), respectively. Bleeding anomalies have been frequently reported in NS, but causes remain unclear. This study investigates platelet activation in patients with NS and NSML and in 2 mouse models carrying PTPN11 mutations responsible for these 2 syndromes. Platelets from NS mice and patients displayed a significant reduction in aggregation induced by low concentrations of GPVI and CLEC-2 agonists and a decrease in thrombus growth on a collagen surface under arterial shear stress. This was associated with deficiencies in GPVI and alphaIIbbeta3 integrin signaling, platelet secretion, and thromboxane A2 generation. Similarly, arterial thrombus formation was significantly reduced in response to a local carotid injury in NS mice, associated with a significant increase in tail bleeding time. In contrast, NSML mouse platelets exhibited increased platelet activation after GPVI and CLEC-2 stimulation and enhanced platelet thrombotic phenotype on collagen matrix under shear stress. Blood samples from NSML patients also showed a shear stress-dependent elevation of platelet responses on collagen matrix. This study brings new insights into the understanding of SHP2 function in platelets, points to new thrombopathies linked to platelet signaling defects, and provides important information for the medical care of patients with NS in situations involving risk of bleeding. CI - (c) 2019 by The American Society of Hematology. FAU - Bellio, Marie AU - Bellio M AD - Institut des Maladies Metaboliques et Cardiovasculaires, INSERM U1048 and Universite Paul Sabatier, Toulouse, France. FAU - Garcia, Cedric AU - Garcia C AD - Laboratoire d'Hematologie, Centre de Reference des Pathologies Plaquettaires. FAU - Edouard, Thomas AU - Edouard T AD - Endocrine, Bone Diseases, and Genetics Unit, Children's Hospital, Hopital Universitaire de Toulouse, Toulouse, France. FAU - Voisin, Sophie AU - Voisin S AD - Laboratoire d'Hematologie, Centre de Reference des Pathologies Plaquettaires. FAU - Neel, Benjamin G AU - Neel BG AD - Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY. FAU - Cabou, Cendrine AU - Cabou C AD - Institut des Maladies Metaboliques et Cardiovasculaires, INSERM U1048 and Universite Paul Sabatier, Toulouse, France. FAU - Valet, Philippe AU - Valet P AD - Institut des Maladies Metaboliques et Cardiovasculaires, INSERM U1048 and Universite Paul Sabatier, Toulouse, France. FAU - Mori, Jun AU - Mori J AD - Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; and. FAU - Mazharian, Alexandra AU - Mazharian A AD - Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; and. AD - UMR_S1255, INSERM, Federation de Medecine Translationnelle de Strasbourg, Universite de Strasbourg and Etablissement Francais du Sang-Grand Est, Strasbourg, France. FAU - Senis, Yotis A AU - Senis YA AD - Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; and. AD - UMR_S1255, INSERM, Federation de Medecine Translationnelle de Strasbourg, Universite de Strasbourg and Etablissement Francais du Sang-Grand Est, Strasbourg, France. FAU - Yart, Armelle AU - Yart A AD - Institut des Maladies Metaboliques et Cardiovasculaires, INSERM U1048 and Universite Paul Sabatier, Toulouse, France. FAU - Payrastre, Bernard AU - Payrastre B AD - Institut des Maladies Metaboliques et Cardiovasculaires, INSERM U1048 and Universite Paul Sabatier, Toulouse, France. AD - Laboratoire d'Hematologie, Centre de Reference des Pathologies Plaquettaires. FAU - Severin, Sonia AU - Severin S AD - Institut des Maladies Metaboliques et Cardiovasculaires, INSERM U1048 and Universite Paul Sabatier, Toulouse, France. LA - eng GR - RG/15/13/31673/BHF_/British Heart Foundation/United Kingdom GR - FS/15/58/31784/BHF_/British Heart Foundation/United Kingdom GR - FS/13/1/29894/BHF_/British Heart Foundation/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood JT - Blood JID - 7603509 RN - EC 3.1.3.48 (PTPN11 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) RN - EC 3.1.3.48 (Ptpn11 protein, mouse) SB - IM CIN - Blood. 2019 Dec 19;134(25):2231-2232. PMID: 31856271 EIN - Blood. 2020 Jun 11;135(24):2197-2198. PMID: 32526025 MH - Animals MH - Blood Platelets/*enzymology/pathology MH - *Germ-Line Mutation MH - Humans MH - Mice MH - Mice, Mutant Strains MH - Noonan Syndrome/*enzymology/pathology MH - Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics/*metabolism MH - *Signal Transduction EDAT- 2019/09/29 06:00 MHDA- 2020/03/25 06:00 CRDT- 2019/09/29 06:00 PHST- 2019/05/10 00:00 [received] PHST- 2019/09/16 00:00 [accepted] PHST- 2019/09/29 06:00 [pubmed] PHST- 2020/03/25 06:00 [medline] PHST- 2019/09/29 06:00 [entrez] AID - S0006-4971(20)73134-4 [pii] AID - 10.1182/blood.2019001543 [doi] PST - ppublish SO - Blood. 2019 Dec 19;134(25):2304-2317. doi: 10.1182/blood.2019001543.