SHP2 sails from physiology to pathology

European Journal of Medical Genetics

Volumn 58, Issue 10, 2015, Pages 509-525

  Tajan, Mylène ^a,b   de Rocca Serra, Audrey ^a,b   Valet, Philippe ^a,b   Edouard, Thomas ^a,c   Yart, Armelle ^a,b  

^a INSERM   (France)

^b Departments of Clinical Biochemistry and Sports Medicine   (France)

^c CHU PURPAN   (France)

Author keywords

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

Indexed keywords

GROWTH FACTOR; HORMONE; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN TYROSINE PHOSPHATASE SHP 2; RAS PROTEIN; PTPN11 PROTEIN, HUMAN;

AUTOSOMAL DOMINANT DISORDER; CARCINOGENESIS; CRANIOFACIAL MALFORMATION; GAIN OF FUNCTION MUTATION; GENE; GENE MUTATION; GENETIC DISORDER; GROWTH RETARDATION; HEART DISEASE; HOMEOSTASIS; HUMAN; INTRACELLULAR SIGNALING; JUVENILE MYELOMONOCYTIC LEUKEMIA; LENTIGO; LEOPARD SYNDROME; LOSS OF FUNCTION MUTATION; METACHONDROMATOSIS; MOLECULAR PATHOLOGY; NONHUMAN; NOONAN SYNDROME; NOONAN SYNDROME WITH MULTIPLE LENTIGINES; PATHOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY; POINT MUTATION; PROTEIN FUNCTION; PROTEIN STRUCTURE; PTPN11 GENE; REVIEW; SIGNAL TRANSDUCTION; SOMATIC MUTATION; AMINO ACID SEQUENCE; ANIMAL; CHEMISTRY; GENETICS; METABOLISM; MOLECULAR GENETICS; MUTATION;

AMINO ACID SEQUENCE; ANIMALS; HUMANS; MOLECULAR SEQUENCE DATA; MUTATION; NOONAN SYNDROME; PROTEIN TYROSINE PHOSPHATASE, NON-RECEPTOR TYPE 11; SIGNAL TRANSDUCTION;

EID: 84945911163     PISSN: 17697212     EISSN: 18780849     Source Type: Journal    
DOI: 10.1016/j.ejmg.2015.08.005     Document Type: Review

References (233)

1. Aceto N., Sausgruber N., Brinkhaus H., Gaidatzis D., Martiny-Baron G., Mazzarol G., et al. Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop. Nat. Med. 2012, 18:529-537.
2. Agazie Y.M., Hayman M.J. Molecular mechanism for a role of SHP2 in epidermal growth factor receptor signaling. Mol. Cell Biol. 2003, 23:7875-7886.
3. Ahmad F., Goldstein B.J. Alterations in specific protein-tyrosine phosphatases accompany insulin resistance of streptozotocin diabetes. Am. J. Physiol. 1995, 268:E932-E940.
4. Ahmad F., Goldstein B.J. Increased abundance of specific skeletal muscle protein-tyrosine phosphatases in a genetic model of insulin-resistant obesity and diabetes mellitus. Metabolism Clin. Exp. 1995, 44:1175-1184.
5. Allard J.D., Chang H.C., Herbst R., McNeill H., Simon M.A. The SH2-containing tyrosine phosphatase corkscrew is required during signaling by sevenless. Ras1 Raf. Dev. (Cambridge, England) 1996, 122:1137-1146.
6. Allison M.B., Myers M.G. 20 years of leptin: connecting leptin signaling to biological function. J. Endocrinol. 2014, 223:T25-T35.
7. Aoki Y., Niihori T., Banjo T., Okamoto N., Mizuno S., Kurosawa K., et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am. J. Hum. Genet. 2013, 93:173-180.
8. Araki T., Chan G., Newbigging S., Morikawa L., Bronson R.T., Neel B.G. Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:4736-4741.
9. Araki T., Mohi M.G., Ismat F.A., Bronson R.T., Williams I.R., Kutok J.L., et al. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat. Med. 2004, 10:849-857.
10. Araki T., Nawa H., Neel B.G. Tyrosyl phosphorylation of Shp2 is required for normal ERK activation in response to some, but not all, growth factors. J. Biol. Chem. 2003, 278:41677-41684.
11. Arrandale J.M., Gorewillse A., Rocks S., Ren J.M., Zhu J., Davis A., et al. Insulin signaling in mice expressing reduced levels of syp. J. Biol. Chem. 1996, 271:21353-21358.
12. Banno R., Zimmer D., De Jonghe B.C., Atienza M., Rak K., Yang W., et al. PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. J. Clin. Invest. 2010, 120:720-734.
13. Bard-Chapeau E.A., Li S., Ding J., Zhang S.S., Zhu H.H., Princen F., et al. Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell 2011, 19:629-639.
14. Bard-Chapeau E.A., Yuan J., Droin N., Long S., Zhang E.E., Nguyen T.V., et al. Concerted functions of Gab1 and Shp2 in liver regeneration and hepatoprotection. Mol. Cell Biol. 2006, 26:4664-4674.
15. Barford D., Neel B.G. Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2. Structure 1998, 6:249-254.
16. Bauer A.J., Stratakis C.A. The lentiginoses: cutaneous markers of systemic disease and a window to new aspects of tumourigenesis. J. Med. Genet. 2005, 42:801-810.
17. Bauler T.J., Kamiya N., Lapinski P.E., Langewisch E., Mishina Y., Wilkinson J.E., et al. Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations. Dis. Models Mech. 2011, 4:228-239.
18. Bennett A.M., Tang T.L., Sugimoto S., Walsh C.T., Neel B.G. Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras. Proc. Natl. Acad. Sci. U. S. A. 1994, 91:7335-7339.
19. Bettaieb A., Matsuo K., Matsuo I., Nagata N., Chahed S., Liu S., et al. Adipose-specific deletion of Src homology phosphatase 2 does not significantly alter systemic glucose homeostasis. Metabolism Clin. Exp. 2011, 286:9225-9235.
20. Bifulco G., Di Carlo C., Caruso M., Oriente F., Di Spiezio Sardo A., Formisano P., et al. Glucose regulates insulin mitogenic effect by modulating SHP-2 activation and localization in JAr cells. J. Biol. Chem. 2002, 277:24306-24314.
21. Binder G., Grathwol S., von Loeper K., Blumenstock G., Kaulitz R., Freiberg C., et al. Health and quality of life in adults with Noonan syndrome. J. Pediatr. 2012, 161:501-505.
22. Bonetti M., Paardekooper Overman J., Tessadori F., Noel E., Bakkers J., den Hertog J. Noonan and LEOPARD syndrome Shp2 variants induce heart displacement defects in zebrafish. Development (Cambridge, England) 2014, 141:1961-1970.
23. Bonetti M., Rodriguez-Martinez V., Paardekooper Overman J., Overvoorde J., van Eekelen M., Jopling C., et al. Distinct and overlapping functions of ptpn11 genes in Zebrafish development. PloS one 2014, 9:e94884.
24. Bonini J.A., Colca J., Hofmann C. Altered expression of insulin signaling components in streptozotocin-treated rats. Biochem. Biophys. Res. Commun. 1995, 212:933-938.
25. Bonini J.A., Colca J.R., Dailey C., White M., Hofmann C. Compensatory alterations for insulin signal transduction and glucose transport in insulin-resistant diabetes. Am. J. Physiol. 1995, 269:E759-E765.
26. Bowen M.E., Ayturk U.M., Kurek K.C., Yang W., Warman M.L. SHP2 regulates chondrocyte terminal differentiation, growth plate architecture and skeletal cell fates. PLoS Genet. 2014, 10:e1004364.
27. Bowen M.E., Boyden E.D., Holm I.A., Campos-Xavier B., Bonafe L., Superti-Furga A., et al. Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. PLoS Genet. 2011, 7:e1002050.
28. Carcavilla A., Santome J.L., Pinto I., Sanchez-Pozo J., Guillen-Navarro E., Martin-Frias M., et al. LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy. Rev. Espanola Cardiol. (English ed) 2013, 66:350-356.
29. Carvajal-Vergara X., Sevilla A., D'Souza S.L., Ang Y.S., Schaniel C., Lee D.F., et al. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 2010, 465:808-812.
30. Chan G., Cheung L.S., Yang W., Milyavsky M., Sanders A.D., Gu S., et al. Essential role for Ptpn11 in survival of hematopoietic stem and progenitor cells. Blood 2011, 117:4253-4261.
31. Chan G., Kalaitzidis D., Usenko T., Kutok J.L., Yang W., Mohi M.G., et al. Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis. Blood 2009, 113:4414-4424.
32. Chan R.J., Li Y., Hass M.N., Walter A., Voorhorst C.S., Shelley W.C., et al. Shp-2 heterozygous hematopoietic stem cells have deficient repopulating ability due to diminished self-renewal. Exp. Hematol. 2006, 34:1230-1239.
33. Chen H., Wertheimer S.J., Lin C.H., Katz S.L., Amrein K.E., Burn P., et al. Protein-tyrosine phosphatases PTP1B and syp are modulators of insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. J. Biol. Chem. 1997, 272:8026-8031.
34. Chen P.C., Wakimoto H., Conner D., Araki T., Yuan T., Roberts A., et al. Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome-associated Sos1 mutation. J. Clin. Invest. 2011, 120:4353-4365.
35. Choi W.W., Yoo J.Y., Park K.C., Kim K.H. LEOPARD syndrome with a new association of congenital corneal tumor, choristoma. Pediatr. Dermatol. 2003, 20:158-160.
36. Choudhry K.S., Grover M., Tran A.A., O'Brian Smith E., Ellis K.J., Lee B.H. Decreased bone mineralization in children with Noonan syndrome: another consequence of dysregulated RAS MAPKinase pathway?. Mol. Genet. Metabolism 2012, 106:237-240.
37. Cleghon V., Feldmann P., Ghiglione C., Copeland T.D., Perrimon N., Hughes D.A., et al. Opposing actions of Csw and RasGAP modulate the strength of torso RTK signaling in the drosophila terminal pathway. Cell 1998, 2:719-727.
38. Cooke M., Orlando U., Maloberti P., Podesta E.J., Cornejo Maciel F. Tyrosine phosphatase SHP2 regulates the expression of acyl-CoA synthetase ACSL4. J. Lipid Res. 2011, 52:1936-1948.
39. Coulombe G., Leblanc C., Cagnol S., Maloum F., Lemieux E., Perreault N., et al. Epithelial tyrosine phosphatase SHP-2 protects against intestinal inflammation in mice. Mol. Cell. Biol. 2013, 33:2275-2284.
40. Cunnick J.M., Dorsey J.F., Munoz-Antonia T., Mei L., Wu J. Requirement of SHP2 binding to Gab1 for MAPK activation in response to LPA and EGF. J. Biol. Chem. 2000, 275:13842-13848.
41. Cunnick J.M., Mei L., Doupnik C.A., Wu J. Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2. J. Biol. Chem. 2001, 276:24380-24387.
42. Cunnick J.M., Meng S., Ren Y., Desponts C., Wang H.G., Djeu J.Y., et al. Regulation of the mitogen-activated protein kinase signaling pathway by SHP2. J. Biol. Chem. 2002, 277:9498-9504.
43. Dance M., Montagner A., Salles J.P., Yart A., Raynal P. The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal 2008, 20:453-459.
44. Darian E., Guvench O., Yu B., Qu C.K., MacKerell A.D. Structural mechanism associated with domain opening in gain-of-function mutations in SHP2 phosphatase. Proteins 2011, 79:1573-1588.
45. Dasgupta B., Yi Y., Chen D.Y., Weber J.D., Gutmann D.H. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res. 2005, 65:2755-2760.
46. De Rocca Serra-Nedelec A., Edouard T., Treguer K., Tajan M., Araki T., Dance M., et al. Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature. Proc. Natl. Acad. Sci. U. S. A. 2012, 109:4257-4262.
47. de Vries A.C., Zwaan C.M., van den Heuvel-Eibrink M.M. Molecular basis of juvenile myelomonocytic leukemia. Haematologica 2010, 95:179-182.
48. Deb T.B., Wong L., Salomon D.S., Zhou G.C., Dixon J.E., Gutkind J.S., et al. A common requirement for the catalytic activity and both SH2 domains of SHP-2 in MAP kinase activation by the ErbB family of receptors. J. Biol. Chem. 1998, 273:16643-16646.
49. Digilio M.C., Sarkozy A., de Zorzi A., Pacileo G., Limongelli G., Mingarelli R., et al. LEOPARD syndrome: clinical diagnosis in the first year of life. Am. J. Med. Genet. A 2006, 140:740-746.
50. do Carmo J.M., da Silva A.A., Ebaady S.E., Sessums P.O., Abraham R.S., Elmquist J.K., et al. Shp2 signaling in POMC neurons is important for leptin's actions on blood pressure, energy balance, and glucose regulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014, 307:R1438-R1447.
51. Duarte A., Poderoso C., Cooke M., Soria G., Cornejo Maciel F., Gottifredi V., et al. Mitochondrial fusion is essential for steroid biosynthesis. PloS One 2012, 7:e45829.
52. Edouard T., Combier J.P., Nedelec A., Bel-Vialar S., Metrich M., Conte-Auriol F., et al. Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling. Mol. Cell Biol. 2010, 30:2498-2507.
53. Edouard T., Montagner A., Dance M., Conte F., Yart A., Parfait B., et al. How do Shp2 mutations that oppositely influence its biochemical activity result in syndromes with overlapping symptoms?. Cell Mol. Life Sci. 2007, 64:1585-1590.
54. Ehrman L.A., Nardini D., Ehrman S., Rizvi T.A., Gulick J., Krenz M., et al. The protein tyrosine phosphatase Shp2 is required for the generation of oligodendrocyte progenitor cells and myelination in the mouse telencephalon. J. Neurosci. 2014, 34:3767-3778.
55. Ekman S., Kallin A., Engstrom U., Heldin C.H., Ronnstrand L. SHP-2 is involved in heterodimer specific loss of phosphorylation of Tyr771 in the PDGF beta-receptor. Oncogene 2002, 21:1870-1875.
56. Eminaga S., Bennett A.M. Noonan syndrome-associated SHP-2/Ptpn11 mutants enhance SIRPalpha and PZR tyrosyl phosphorylation and promote adhesion-mediated ERK activation. J. Biol. Chem. 2008, 283:15328-15338.
57. Feng G.S., Hui C.C., Pawson T. SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science 1993, 259:1607-1611.
58. Fornaro M., Burch P.M., Yang W., Zhang L., Hamilton C.E., Kim J.H., et al. SHP-2 activates signaling of the nuclear factor of activated T cells to promote skeletal muscle growth. J. Cell Biol. 2006, 175:87-97.
59. Fragale A., Tartaglia M., Wu J., Gelb B.D. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum. Mutat. 2004, 23:267-277.
60. Fukunaga K., Noguchi T., Takeda H., Matozaki T., Hayashi Y., Itoh H., et al. Requirement for protein-tyrosine phosphatase SHP-2 in insulin-induced activation of c-Jun NH(2)-terminal kinase. J. Biol. Chem. 2000, 275:5208-5213.
61. Gauthier A.S., Furstoss O., Araki T., Chan R., Neel B.G., Kaplan D.R., et al. Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome. Neuron 2007, 54:245-262.
62. Gomes E.G., Connelly S.F., Summy J.M. Targeting the yin and the yang: combined inhibition of the tyrosine kinase c-Src and the tyrosine phosphatase SHP-2 disrupts pancreatic cancer signaling and biology in vitro and tumor formation in vivo. Pancreas 2013, 42:795-806.
63. Grossmann K.S., Rosario M., Birchmeier C., Birchmeier W. The tyrosine phosphatase Shp2 in development and cancer. Adv. Cancer Res. 2010, 106:53-89.
64. Grossmann K.S., Wende H., Paul F.E., Cheret C., Garratt A.N., Zurborg S., et al. The tyrosine phosphatase Shp2 (PTPN11) directs Neuregulin-1/ErbB signaling throughout Schwann cell development. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:16704-16709.
65. Gu J., Han T., Ma R.H., Zhu Y.L., Jia Y.N., Du J.J., et al. SHP2 promotes laryngeal cancer growth through the Ras/Raf/Mek/Erk pathway and serves as a prognostic indicator for laryngeal cancer. Int. J. Oncol. 2014, 44:481-490.
66. Gutch M.J., Flint A.J., Keller J., Tonks N.K., Hengartner M.O. The Caenorhabditis elegans SH2 domain-containing protein tyrosine phosphatase PTP-2 participates in signal transduction during oogenesis and vulval development. Genes & Dev. 1998, 12:571-585.
67. Hagihara K., Zhang E.E., Ke Y.H., Liu G., Liu J.J., Rao Y., et al. Shp2 acts downstream of SDF-1alpha/CXCR4 in guiding granule cell migration during cerebellar development. Dev. Biol. 2009, 334:276-284.
68. Hahn A., Lauriol J., Thul J., Behnke-Hall K., Logeswaran T., Schanzer A., et al. Rapidly progressive hypertrophic cardiomyopathy in an infant with noonan syndrome with multiple lentigines: palliative treatment with a rapamycin analog. Am. J. Med. Genet. 2015, 67A:744-751.
69. Hanafusa H., Torii S., Yasunaga T., Matsumoto K., Nishida E. Shp2, an SH2-containing protein tyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor sprouty. J. Biol. Chem. 2004, 279:22992-22995.
70. Hanna N., Montagner A., Lee W.H., Miteva M., Vidal M., Vidaud M., et al. Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett. 2006, 580:2477-2482.
71. Hausdorff S.F., Bennett A.M., Neel B.G., Birnbaum M.J. Different signaling roles of SHPTP2 in insulin-induced GLUT1 expression and GLUT4 translocation. J. Biol. Chem. 1995, 270:12965-12968.
72. He Z., Zhang S.S., Meng Q., Li S., Zhu H.H., Raquil M.A., et al. Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals. Mol. Cell. Biol. 2012, 32:1867-1878.
73. He Z., Zhu H.H., Bauler T.J., Wang J., Ciaraldi T., Alderson N., et al. Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase. Proc. Natl. Acad. Sci. U. S. A. 2012, 110:E79-E88.
74. Herbst R., Carroll P.M., Allard J.D., Schilling J., Raabe T., Simon M.A. Daughter of sevenless is a substrate of the phosphotyrosine phosphatase corkscrew and functions during sevenless signaling. Cell 1996, 85:899-909.
75. Heuberger J., Kosel F., Qi J., Grossmann K.S., Rajewsky K., Birchmeier W. Shp2/MAPK signaling controls goblet/paneth cell fate decisions in the intestine. Proc. Natl. Acad. Sci. U. S. A. 2014, 111:3472-3477.
76. Hof P., Pluskey S., Dhe-Paganon S., Eck M.J., Shoelson S.E. Crystal structure of the tyrosine phosphatase SHP-2. Cell 1998, 92:441-450.
77. Hu Z., Fang H., Wang X., Chen D., Chen Z., Wang S. Overexpression of SHP2 tyrosine phosphatase promotes the tumorigenesis of breast carcinoma. Oncol. Rep. 2014, 32:205-212.
78. Huang Y.S., Cheng C.Y., Chueh S.H., Hueng D.Y., Huang Y.F., Chu C.M., et al. Involvement of SHP2 in focal adhesion, migration and differentiation of neural stem cells. Brain Dev. 2012, 34:674-684.
79. Hugues L., Cave H., Philippe N., Pereira S., Fenaux P., Preudhomme C. Mutations of PTPN11 are rare in adult myeloid malignancies. Haematologica 2005, 90:853-854.
80. Ishida H., Kogaki S., Narita J., Ichimori H., Nawa N., Okada Y., et al. LEOPARD-type SHP2 mutant Gln510Glu attenuates cardiomyocyte differentiation and promotes cardiac hypertrophy via dysregulation of Akt/GSK-3beta/beta-catenin signaling. Am. J. Physiol. Heart Circ. Physiol. 2011, 301:H1531-H1539.
81. Jamshidi Y., Gooljar S.B., Snieder H., Wang X., Ge D., Swaminathan R., et al. SHP-2 and PI3-kinase genes PTPN11 and PIK3R1 may influence serum apoB and LDL cholesterol levels in normal women. Atherosclerosis 2007, 194:e26-33.
82. Jang J.Y., Min J.H., Chae Y.H., Baek J.Y., Wang S.B., Park S.J., et al. Reactive oxygen species play a critical role in collagen-induced platelet activation via SHP-2 oxidation. Antioxidants Redox Signal. 2014, 20:2528-2540.
83. Jia Z.F., Cao X.Y., Cao D.H., Kong F., Kharbuja P., Jiang J. Polymorphisms of PTPN11 gene could influence serum lipid levels in a sex-specific pattern. Lipids Health Dis. 2013, 12:72.
84. Jopling C., van Geemen D., den Hertog J. Shp2 knockdown and Noonan/LEOPARD mutant Shp2-induced gastrulation defects. PLoS Genet. 2007, 3:e225.
85. Kamiya N., Kim H.K., King P.D. Regulation of bone and skeletal development by the SHP-2 protein tyrosine phosphatase. Bone 2014, 69:55-60.
86. Kamiya N., Shen J., Noda K., Kitami M., Feng G.S., Chen D., et al. SHP2-Deficiency in chondrocytes deforms orofacial cartilage and ciliogenesis in mice. J. Bone Min. Res. 2015, http://dx.doi.org/10.1002/jbmr.2541.
87. Ke Y., Lesperance J., Zhang E.E., Bard-Chapeau E.A., Oshima R.G., Muller W.J., et al. Conditional deletion of Shp2 in the mammary gland leads to impaired lobulo-alveolar outgrowth and attenuated Stat5 activation. J. Biol. Chem. 2006, 281:34374-34380.
88. Ke Y., Zhang E.E., Hagihara K., Wu D., Pang Y., Klein R., et al. Deletion of Shp2 in the brain leads to defective proliferation and differentiation in neural stem cells and early postnatal lethality. Mol. Cell. Biol. 2007, 27:6706-6717.
89. Keilhack H., David F.S., McGregor M., Cantley L.C., Neel B.G. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J. Biol. Chem. 2005, 280:30984-30993.
90. Kim H.K., Aruwajoye O., Sucato D., Richards B.S., Feng G.S., Chen D., et al. Induction of SHP2 deficiency in chondrocytes causes severe scoliosis and kyphosis in mice. Spine 2013, 38:E1307-E1312.
91. Kim H.K., Feng G.S., Chen D., King P.D., Kamiya N. Targeted disruption of Shp2 in chondrocytes leads to metachondromatosis with multiple cartilaginous protrusions. J. Bone Min. Res. 2014, 29:761-769.
92. Kontaridis M.I., Eminaga S., Fornaro M., Zito C.I., Sordella R., Settleman J., et al. SHP-2 positively regulates myogenesis by coupling to the Rho GTPase signaling pathway. Mol. Cell. Biol. 2004, 24:5340-5352.
93. Kontaridis M.I., Swanson K.D., David F.S., Barford D., Neel B.G. PTPN11 (SHP2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J. Biol. Chem. 2006, 281:6785-6792.
94. Kontaridis M.I., Yang W., Bence K.K., Cullen D., Wang B., Bodyak N., et al. Deletion of Ptpn11 (Shp2) in cardiomyocytes causes dilated cardiomyopathy via effects on the extracellular signal-regulated kinase/mitogen-activated protein kinase and RhoA signaling pathways. Circulation 2008, 117:1423-1435.
95. Koudova M., Seemanova E., Zenker M. Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence. Eur. J. Med. Genet. 2009, 52:337-340.
96. Kraja A.T., Chasman D.I., North K.E., Reiner A.P., Yanek L.R., Kilpelainen T.O., et al. Pleiotropic genes for metabolic syndrome and inflammation. Mol. Genet. Metabolism 2014, 112:317-338.
97. Krajewska M., Banares S., Zhang E.E., Huang X., Scadeng M., Jhala U.S., et al. Development of diabesity in mice with neuronal deletion of Shp2 tyrosine phosphatase. Am. J. Pathol. 2008, 172:1312-1324.
98. Kratz C.P., Franke L., Peters H., Kohlschmidt N., Kazmierczak B., Finckh U., et al. Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes. Br. J. Cancer 2015, 112:1392-1397.
99. Krenz M., Gulick J., Osinska H.E., Colbert M.C., Molkentin J.D., Robbins J. Role of ERK1/2 signaling in congenital valve malformations in Noonan syndrome. Proc. Natl. Acad. Sci. U. S. A. 2008, 105:18930-18935.
100. Krenz M., Yutzey K.E., Robbins J. Noonan syndrome mutation Q79R in Shp2 increases proliferation of valve primordia mesenchymal cells via extracellular signal-regulated kinase 1/2 signaling. Circ. Res. 2005, 97:813-820.
101. Kwon J., Qu C.K., Maeng J.S., Falahati R., Lee C., Williams M.S. Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76-ADAP. EMBO J. 2005, 24:2331-2341.
102. Lajiness J.D., Snider P., Wang J., Feng G.S., Krenz M., Conway S.J. SHP-2 deletion in postmigratory neural crest cells results in impaired cardiac sympathetic innervation. Proc. Natl. Acad. Sci. U. S. A. 2014, 111:E1374-1382.
103. Langdon Y., Tandon P., Paden E., Duddy J., Taylor J.M., Conlon F.L. SHP-2 acts via ROCK to regulate the cardiac actin cytoskeleton. Development (Cambridge, England) 2012, 139:948-957.
104. Lapinski P.E., Meyer M.F., Feng G.S., Kamiya N., King P.D. Deletion of SHP-2 in mesenchymal stem cells causes growth retardation, limb and chest deformity, and calvarial defects in mice. Dis. Models Mech. 2013, 6:1448-1458.
105. Lauriol J., Jaffre F., Kontaridis M.I. The role of the protein tyrosine phosphatase SHP2 in cardiac development and disease. Seminars Cell Dev. Biol. 2014, 37C:73-81.
106. Lauriol J., Kontaridis M.I. PTPN11-associated mutations in the heart: has LEOPARD changed its RASpots?. Trends Cardiovasc. Med. 2011, 21:97-104.
107. Laux D., Kratz C., Sauerbrey A. Common acute lymphoblastic leukemia in a girl with genetically confirmed LEOPARD syndrome. J. Pediatr. Hematol. Oncol. 2008, 30:602-604.
108. Lee I., Pecinova A., Pecina P., Neel B.G., Araki T., Kucherlapati R., et al. A suggested role for mitochondria in Noonan syndrome. Biochim. Biophys. Acta 2010, 1802:275-283.
109. Lee Y.S., Ehninger D., Zhou M., Oh J.Y., Kang M., Kwak C., et al. Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome. Nat. Neurosci. 2014, 17:1736-1743.
110. Li S., Hsu D.D., Li B., Luo X., Alderson N., Qiao L., et al. Cytoplasmic tyrosine phosphatase Shp2 coordinates hepatic regulation of bile acid and FGF15/19 signaling to repress bile acid synthesis. Cell Metab. 2014, 20:320-332.
111. Li W., Cui Y., Kushner S.A., Brown R.A., Jentsch J.D., Frankland P.W., et al. The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr. Biol. 2005, 15:1961-1967.
112. Li W., Nishimura R., Kashishian A., Batzer A.G., Kim W.J., Cooper J.A., et al. A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase. Mol. Cell Biol. 1994, 14:509-517.
113. Limongelli G., Pacileo G., Marino B., Digilio M.C., Sarkozy A., Elliott P., et al. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. Am. J. Cardiol. 2007, 100:736-741.
114. Limongelli G., Sarkozy A., Pacileo G., Calabro P., Digilio M.C., Maddaloni V., et al. Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome. Am. J. Med. Genet. 2008, 146A:620-628.
115. Lindhurst M.J., Parker V.E., Payne F., Sapp J.C., Rudge S., Harris J., et al. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat. Genet. 2012, 44:928-933.
116. Lindhurst M.J., Sapp J.C., Teer J.K., Johnston J.J., Finn E.M., Peters K., et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 2011, 365:611-619.
117. Liu K.W., Feng H., Bachoo R., Kazlauskas A., Smith E.M., Symes K., et al. SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans. J. Clin. Invest. 2011, 121:905-917.
118. Loh M.L., Reynolds M.G., Vattikuti S., Gerbing R.B., Alonzo T.A., Carlson E., et al. PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. Leukemia 2004, 18:1831-1834.
119. Loh M.L., Vattikuti S., Schubbert S., Reynolds M.G., Carlson E., Lieuw K.H., et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 2004, 103:2325-2331.
120. Lu H.S., Saito Y., Umeda M., Murata-Kamiya N., Zhang H.M., Higashi H., et al. Structural and functional diversity in the PAR1b/MARK2-binding region of Helicobacter pylori CagA. Cancer Sci. 2008, 99:2004-2011.
121. Lu W., Gong D., Bar-Sagi D., Cole P.A. Site-specific incorporation of a phosphotyrosine mimetic reveals a role for tyrosine phosphorylation of SHP-2 in cell signaling. Mol. Cell 2001, 8:759-769.
122. Maegawa H., Hasegawa M., Sugai S., Obata T., Ugi S., Morino K., et al. Expression of a dominant negative SHP-2 in transgenic mice induces insulin resistance. J. Biol. Chem. 1999, 274:30236-30243.
123. Maegawa H., Kashiwagi A., Fujita T., Ugi S., Hasegawa M., Obata T., et al. SHPTP2 serves adapter protein linking between Janus kinase 2 and insulin receptor substrates. Biochem. Biophys. Res. Commun. 1996, 228:122-127.
124. Mainberger F., Jung N.H., Zenker M., Wahllander U., Freudenberg L., Langer S., et al. Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1. BMC Neurol. 2013, 13:1-12.
125. Malaquias A.C., Brasil A.S., Pereira A.C., Arnhold I.J., Mendonca B.B., Bertola D.R., et al. Growth standards of patients with Noonan and Noonan-like syndromes with mutations in the RAS/MAPK pathway. Am. J. Med. Genet. 2012, 158A:2700-2706.
126. Marin T.M., Keith K., Davies B., Conner D.A., Guha P., Kalaitzidis D., et al. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J. Clin. Invest. 2011, 121:1026-1043.
127. Maroun C.R., Naujokas M.A., Holgado-Madruga M., Wong A.J., Park M. The tyrosine phosphatase SHP-2 is required for sustained activation of extracellular signal-regulated kinase and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol. Cell Biol. 2000, 20:8513-8525.
128. Martinelli S., Nardozza A.P., Delle Vigne S., Sabetta G., Torreri P., Bocchinfuso G., et al. Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. J. Biol. Chem. 2012, 287:27066-27077.
129. Martinelli S., Torreri P., Tinti M., Stella L., Bocchinfuso G., Flex E., et al. Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes. Hum. Mol. Genet. 2008, 17:2018-2029.
130. Martinez-Quintana E., Rodriguez-Gonzalez F. LEOPARD syndrome: clinical features and gene mutations. Mol. Syndromol. 2012, 3:145-157.
131. Matsuo K., Delibegovic M., Matsuo I., Nagata N., Liu S., Bettaieb A., et al. Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2. J. Biol. Chem. 2010, 285:39750-39758.
132. Mazharian A., Mori J., Wang Y.J., Heising S., Neel B.G., Watson S.P., et al. Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function. Blood 2013, 121:4205-4220.
133. Milarski K.L., Saltiel A.R. Expression of catalytically inactive Syp phosphatase in 3T3 cells blocks stimulation of mitogen-activated protein kinase by insulin. J. Biol. Chem. 1994, 269:21239-21243.
134. Miura K., Wakayama Y., Tanino M., Orba Y., Sawa H., Hatakeyama M., et al. Involvement of EphA2-mediated tyrosine phosphorylation of Shp2 in Shp2-regulated activation of extracellular signal-regulated kinase. Oncogene 2013, 32:5292-5301.
135. Mohi M.G., Williams I.R., Dearolf C.R., Chan G., Kutok J.L., Cohen S., et al. Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer Cell 2005, 7:179-191.
136. Montagner A., Yart A., Dance M., Perret B., Salles J.P., Raynal P. A novel role for Gab1 and SHP2 in EGF-induced Ras activation. J. Biol. Chem. 2005, 280:5350-5360.
137. Mussig K., Staiger H., Fiedler H., Moeschel K., Beck A., Kellerer M., et al. Shp2 is required for protein kinase C-dependent phosphorylation of serine 307 in insulin receptor substrate-1. J. Biol. Chem. 2005, 280:32693-32699.
138. Myers M.G., Mendez R., Shi P., Pierce J.H., Rhoads R., White M.F. The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling. J. Biol. Chem. 1998, 273:26908-26914.
139. Nabinger S.C., Chan R.J. Shp2 function in hematopoietic stem cell biology and leukemogenesis. Curr. Opin. Hematol. 2012, 19:273-279.
140. Nagata N., Matsuo K., Bettaieb A., Bakke J., Matsuo I., Graham J., et al. Hepatic SRC homology phosphatase 2 regulates energy balance in mice. Endocrinology 2012, 153:3158-3169.
141. Nakamura T., Colbert M., Krenz M., Molkentin J.D., Hahn H.S., Dorn G.W., et al. Mediating ERK 1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome. J. Clin. Invest. 2007, 117:2123-2132.
142. Nakamura T., Gulick J., Colbert M.C., Robbins J. Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:11270-11275.
143. Nakamura T., Gulick J., Pratt R., Robbins J. Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:15436-15441.
144. Neel B.G., Gu H., Pao L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 2003, 28:284-293.
145. Nguyen T.V., Ke Y., Zhang E.E., Feng G.S. Conditional deletion of Shp2 tyrosine phosphatase in thymocytes suppresses both pre-TCR and TCR signals. J. Immunol. 2006, 177:5990-5996.
146. Niihori T., Aoki Y., Ohashi H., Kurosawa K., Kondoh T., Ishikiriyama S., et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. J. Hum. Genet. 2005, 50:192-202.
147. Noguchi T., Matozaki T., Horita K., Fujioka Y., Kasuga M. Role of SH-PTP2, a protein-tyrosine phosphatase with src homology 2 domains, in insulin-stimulated ras activation. Mol. Cell Biol. 1994, 14:6674-6682.
148. Noonan J.A. Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Am. J. Dis. Child. 1968, 116:373-380.
149. Noonan J.A., Kappelgaard A.M. The efficacy and Safety of growth hormone therapy in children with Noonan syndrome: a review of the evidence. Hormone Res. Paediatr. 2014, 83:157-166.
150. O'Reilly A.M., Pluskey S., Shoelson S.E., Neel B.G. Activated mutants of SHP-2 preferentially induce elongation of Xenopus animal caps. Mol. Cell. Biol. 2000, 20:299-311.
151. Oishi K., Gaengel K., Krishnamoorthy S., Kamiya K., Kim I.K., Ying H., et al. Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations. Hum. Mol. Genet. 2006, 15:543-553.
152. Oishi K., Zhang H., Gault W.J., Wang C.J., Tan C.C., Kim I.K., et al. Phosphatase-defective LEOPARD syndrome mutations in PTPN11 have gain-of-function effects during Drosophila development. Hum. Mol. Genet. 2008, 8:193-201.
153. Ouwens D.M., van der Zon G.C., Maassen J.A. Modulation of insulin-stimulated glycogen synthesis by Src homology phosphatase 2. Mol. Cell. Endocrinol. 2001, 175:131-140.
154. Paardekooper Overman J., Yi J.S., Bonetti M., Soulsby M., Preisinger C., Stokes M.P., et al. PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice. Mol. Cell. Biol. 2014, 34:2874-2889.
155. Pagani M.R., Oishi K., Gelb B.D., Zhong Y. The phosphatase SHP2 regulates the spacing effect for long-term memory induction. Cell 2009, 139:186-198.
156. Pal A., Barber T.M., Van de Bunt M., Rudge S.A., Zhang Q., Lachlan K.L., et al. PTEN mutations as a cause of constitutive insulin sensitivity and obesity. N. Engl. J. Med. 2012, 367:1002-1011.
157. Pandit B., Sarkozy A., Pennacchio L.A., Carta C., Oishi K., Martinelli S., et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat. Genet. 2007, 39:1007-1012.
158. Peraldi P., Zhao Z., Filloux C., Fischer E.H., Van Obberghen E. Protein-tyrosine-phosphatase 2C is phosphorylated and inhibited by 44-kDa mitogen-activated protein kinase. Proc. Natl. Acad. Sci. U. S. A. 1994, 91:5002-5006.
159. Perkins L.A., Johnson M.R., Melnick M.B., Perrimon N. The nonreceptor protein tyrosine phosphatase corkscrew functions in multiple receptor tyrosine kinase pathways in Drosophila. Dev. Biol. 1996, 180:63-81.
160. Perkins L.A., Larsen I., Perrimon N. Corkscrew encodes a putative protein tyrosine phosphatase that functions to transduce the terminal signal from the receptor tyrosine kinase torso. Cell 1992, 70:225-236.
161. Prendiville T.W., Gauvreau K., Tworog-Dube E., Patkin L., Kucherlapati R.S., Roberts A.E., et al. Cardiovascular disease in Noonan syndrome. Arch. Dis. Child. 2014, 99:629-634.
162. Princen F., Bard E., Sheikh F., Zhang S.S., Wang J., Zago W.M., et al. Deletion of Shp2 tyrosine phosphatase in muscle leads to dilated cardiomyopathy, insulin resistance and premature death. Mol. Cell Biol. 2009, 29:378-388.
163. Puri P., Phillips B.T., Suzuki H., Orwig K.E., Rajkovic A., Lapinski P.E., et al. The transition from stem cell to progenitor spermatogonia and male fertility requires the SHP2 protein tyrosine phosphatase. Stem Cells (Dayton, Ohio) 2014, 32:741-753.
164. Qiu W., Wang X., Romanov V., Hutchinson A., Lin A., Ruzanov M., et al. Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct. Biol. 2014, 14.
165. Qu C.K., Nguyen S., Chen J., Feng G.S. Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development. Blood 2001, 97:911-914.
166. Ranke M.B., Heidemann P., Knupfer C., Enders H., Schmaltz A.A., Bierich J.R. Noonan syndrome: growth and clinical manifestations in 144 cases. Eur. J. Pediatr. 1988, 148:220-227.
167. Rauen K.A. The RASopathies. Annu. Rev. Genomics Hum. Genet. 2013, 14:355-369.
168. Ren Y., Meng S., Mei L., Zhao Z.J., Jove R., Wu J. Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor. J. Biol. Chem. 2004, 279:8497-8505.
169. Riviere J.B., Mirzaa G.M., O'Roak B.J., Beddaoui M., Alcantara D., Conway R.L., et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 2012, 44:934-940.
170. Roberts A.E., Allanson J.E., Tartaglia M., Gelb B.D. Noonan syndrome. Lancet 2013, 381:333-342.
171. Romano A.A., Allanson J.E., Dahlgren J., Gelb B.D., Hall B., Pierpont M.E., et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 2010, 126:746-759.
172. Rosenberger G., Meien S., Kutsche K. Oncogenic HRAS mutations cause prolonged PI3K signaling in response to epidermal growth factor in fibroblasts of patients with Costello syndrome. Hum. Mutat. 2009, 30:352-362.
173. Salmond R.J., Huyer G., Kotsoni A., Clements L., Alexander D.R. The src homology 2 domain-containing tyrosine phosphatase 2 regulates primary T-dependent immune responses and Th cell differentiation. J. Immunol. 2005, 175:6498-6508.
174. Salvi M., Stringaro A., Brunati A.M., Agostinelli E., Arancia G., Clari G., et al. Tyrosine phosphatase activity in mitochondria: presence of Shp-2 phosphatase in mitochondria. Cell Mol. Life Sci. 2004, 61:2393-2404.
175. Sarkozy A., Carta C., Moretti S., Zampino G., Digilio M.C., Pantaleoni F., et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum. Mutat. 2009, 30:695-702.
176. Sarkozy A., Conti E., Digilio M.C., Marino B., Morini E., Pacileo G., et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J. Med. Genet. 2004, 41:e68.
177. Sarkozy A., Digilio M.C., Dallapiccola B. Leopard syndrome. Orphanet J. Rare Dis. 2008, 3:13.
178. Sausgruber N., Coissieux M.M., Britschgi A., Wyckoff J., Aceto N., Leroy C., et al. Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases. Oncogene 2014, 34:2272-2278.
179. Saxton T.M., Henkemeyer M., Gasca S., Shen R., Rossi D.J., Shalaby F., et al. Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. EMBO J. 1997, 16:2352-2364.
180. Schramm C., Edwards M.A., Krenz M. New approaches to prevent LEOPARD syndrome-associated cardiac hypertrophy by specifically targeting Shp2-dependent signaling. J. Biol. Chem. 2013, 288:18335-18344.
181. Schramm C., Fine D.M., Edwards M.A., Reeb A.N., Krenz M. The PTPN11 loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling. Am. J. Physiol. Heart Circ. Physiol. 2012, 302:H231-H243.
182. Seishima M., Mizutani Y., Shibuya Y., Arakawa C., Yoshida R., Ogata T. Malignant melanoma in a woman with LEOPARD syndrome: identification of a germline PTPN11 mutation and a somatic BRAF mutation. Br. J. Dermatol. 2007, 157:1297-1299.
183. Sharma N., Everingham S., Ramdas B., Kapur R., Craig A.W. SHP2 phosphatase promotes mast cell chemotaxis toward stem cell factor via enhancing activation of the Lyn/Vav/Rac signaling axis. J. Immunol. 2014, 192:4859-4866.
184. Sharma N., Kumar V., Everingham S., Mali R.S., Kapur R., Zeng L.F., et al. SH2 domain-containing phosphatase 2 is a critical regulator of connective tissue mast cell survival and homeostasis in mice. Mol. Cell. Biol. 2012, 32:2653-2663.
185. Side L.E., Emanuel P.D., Taylor B., Franklin J., Thompson P., Castleberry R.P., et al. Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood 1998, 92:267-272.
186. Sobreira N.L., Cirulli E.T., Avramopoulos D., Wohler E., Oswald G.L., Stevens E.L., et al. Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet. 2010, 6:e1000991.
187. Stevenson D.A., Schwarz E.L., Carey J.C., Viskochil D.H., Hanson H., Bauer S., et al. Bone resorption in syndromes of the Ras/MAPK pathway. Clin. Genet. 2011, 80:566-573.
188. Stewart R.A., Sanda T., Widlund H.R., Zhu S., Swanson K.D., Hurley A.D., et al. Phosphatase-dependent and -independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis. Dev. Cell 2010, 18:750-762.
189. Strullu M., Caye A., Lachenaud J., Cassinat B., Gazal S., Fenneteau O., et al. Juvenile myelomonocytic leukaemia and Noonan syndrome. J. Med. Genet. 2014, 51:689-697.
190. Sun J., Lu S., Ouyang M., Lin L.J., Zhuo Y., Liu B., et al. Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2. Nat. Commun. 2013, 4:2037.
191. Tajan M., Batut A., Cadoudal T., Deleruyelle S., Le Gonidec S., Saint Laurent C., et al. LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity. Proc. Natl. Acad. Sci. U. S. A. 2014, 111:E4494-E4503.
192. Takahashi A., Tsutsumi R., Kikuchi I., Obuse C., Saito Y., Seidi A., et al. SHP2 tyrosine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver. Mol. Cell 2011, 43:45-56.
193. Tang T.L., Freeman R.M., Oreilly A.M., Neel B.G., Sokol S.Y. The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early xenopus development. Cell 1995, 80:473-483.
194. Tartaglia M., Gelb B.D. Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms. Ann. N. Y. Acad. Sci. 2010, 1214:99-121.
195. Tartaglia M., Gelb B.D., Zenker M. Noonan syndrome and clinically related disorders. Best Pract. Res. Clin. Endocrinol. Metab. 2011, 25:161-179.
196. Tartaglia M., Martinelli S., Stella L., Bocchinfuso G., Flex E., Cordeddu V., et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am. J. Hum. Genet. 2006, 78:279-290.
197. Tartaglia M., Niemeyer C.M., Fragale A., Song X., Buechner J., Jung A., et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat. Genet. 2003, 34:148-150.
198. Tartaglia M., Zampino G., Gelb B.D. Noonan syndrome: clinical aspects and molecular pathogenesis. Mol. Syndromol. 2010, 1:2-26.
199. Tefft D., De Langhe S.P., Del Moral P.M., Sala F., Shi W., Bellusci S., et al. A novel function for the protein tyrosine phosphatase Shp2 during lung branching morphogenesis. Dev. Biol. 2005, 282:422-431.
200. Tefft D., Lee M., Smith S., Crowe D.L., Bellusci S., Warburton D. mSprouty2 inhibits FGF10-activated MAP kinase by differentially binding to upstream target proteins. Am. J. Physiol. Lung Cell Mol. Physiol. 2002, 283:L700-L706.
201. Tidyman W.E., Rauen K.A. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr. Opin. Genet. Dev. 2009, 19:230-236.
202. Tsutsumi R., Masoudi M., Takahashi A., Fujii Y., Hayashi T., Kikuchi I., et al. YAP and TAZ, Hippo signaling targets, act as a rheostat for nuclear SHP2 function. Dev. cell 2013, 26:658-665.
203. Ucar C., Calyskan U., Martini S., Heinritz W. Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive). J. Pediatr. Hematol. Oncol. 2006, 28:123-125.
204. Uehara T., Suzuki K., Yamanaka H., Kizaki T., Sakurai T., Ishibashi Y., et al. SHP-2 positively regulates adipogenic differentiation in 3T3-L1 cells. Int. J. Mol. Med. 2007, 19:895-900.
205. Ugi S., Maegawa H., Kashiwagi A., Adachi M., Olefsky J.M., Kikkawa R. Expression of dominant negative mutant SHPTP2 attenuates phosphatidylinositol 3'-kinase activity via modulation of phosphorylation of insulin receptor substrate-1. J. Biol. Chem. 1996, 271:12595-12602.
206. Vogel W., Ullrich A. Multiple in vivo phosphorylated tyrosine phosphatase SHP-2 engages binding to Grb2 via tyrosine 584. Cell Growth Differ. 1996, 7:1589-1597.
207. Willecke R., Heuberger J., Grossmann K., Michos O., Schmidt-Ott K., Walentin K., et al. The tyrosine phosphatase Shp2 acts downstream of GDNF/Ret in branching morphogenesis of the developing mouse kidney. Dev. Biol. 2011, 360:310-317.
208. Witt D.R., Keena B.A., Hall J.G., Allanson J.E. Growth curves for height in Noonan syndrome. Clin. Genet. 1986, 30:150-153.
209. Woywodt A., Welzel J., Haase H., Duerholz A., Wiegand U., Potratz J., et al. Cardiomyopathic lentiginosis/LEOPARD syndrome presenting as sudden cardiac arrest. Chest 1998, 113:1415-1417.
210. Wu D., Pang Y., Ke Y., Yu J., He Z., Tautz L., et al. A conserved mechanism for control of human and mouse embryonic stem cell pluripotency and differentiation by shp2 tyrosine phosphatase. PloS One 2009, 4:e4914.
211. Wu X., Simpson J., Hong J.H., Kim K.H., Thavarajah N.K., Backx P.H., et al. MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation. J. Clin. Invest. 2011, 121:1009-1025.
212. Xu D., Liu X., Yu W.M., Meyerson H.J., Guo C., Gerson S.L., et al. Non-lineage/stage-restricted effects of a gain-of-function mutation in tyrosine phosphatase Ptpn11 (Shp2) on malignant transformation of hematopoietic cells. J. Exp. Med. 2011, 208:1977-1988.
213. Xu D., Qu C.K. Protein tyrosine phosphatases in the JAK/STAT pathway. Front. Biosci. 2008, 13:4925-4932.
214. Xu D., Zheng H., Yu W.M., Qu C.K. Activating mutations in protein tyrosine phosphatase Ptpn11 (Shp2) enhance reactive oxygen species production that contributes to myeloproliferative disorder. PloS One 2013, 8:e63152.
215. Xu R., Yu Y., Zheng S., Zhao X., Dong Q., He Z., et al. Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia. Blood 2005, 106:3142-3149.
216. Yamamoto G.L., Aguena M., Gos M., Hung C., Pilch J., Fahiminiya S., et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 2015, 52:413-421.
217. Yamashita A., Morioka M., Kishi H., Kimura T., Yahara Y., Okada M., et al. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 2014, 513:507-511.
218. Yang W., Klaman L.D., Chen B., Araki T., Harada H., Thomas S.M., et al. An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. Dev. Cell 2006, 10:317-327.
219. Yang W., Wang J., Moore D.C., Liang H., Dooner M., Wu Q., et al. Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling. Nature 2013, 499:491-495.
220. Yang Z., Li Y., Yin F., Chan R.J. Activating PTPN11 mutants promote hematopoietic progenitor cell-cycle progression and survival. Exp. Hematol. 2008, 36:1285-1296.
221. Yu J., Deng R., Zhu H.H., Zhang S.S., Zhu C., Montminy M., et al. Modulation of fatty acid synthase degradation by concerted action of p38 MAP kinase, E3 ligase COP1, and SH2-tyrosine phosphatase Shp2. J. Biol. Chem. 2013, 288:3823-3830.
222. Yu Z.H., Xu J., Walls C.D., Chen L., Zhang S., Zhang R., et al. Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations. J. Biol. Chem. 2013, 288:10472-10482.
223. Zhang E.E., Chapeau E., Hagihara K., Feng G.S. Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc. Natl. Acad. Sci. U. S. A. 2004, 101:16064-16069.
224. Zhang S.Q., Tsiaras W.G., Araki T., Wen G., Minichiello L., Klein R., et al. Receptor-specific regulation of phosphatidylinositol 3'-kinase activation by the protein tyrosine phosphatase Shp2. Mol. Cell Biol. 2002, 22:4062-4072.
225. Zhang S.Q., Yang W., Kontaridis M.I., Bivona T.G., Wen G., Araki T., et al. Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol. Cell 2004, 13:341-355.
226. Zhang S.S., Hao E., Yu J., Liu W., Wang J., Levine F., et al. Coordinated regulation by Shp2 tyrosine phosphatase of signaling events controlling insulin biosynthesis in pancreatic beta-cells. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:7531-7536.
227. Zhang W., Chan R.J., Chen H., Yang Z., He Y., Zhang X., et al. Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia. J. Biol. Chem. 2009, 284:22353-22363.
228. Zhang X., Zhang Y., Tao B., Teng L., Li Y., Cao R., et al. Loss of Shp2 in alveoli epithelia induces deregulated surfactant homeostasis, resulting in spontaneous pulmonary fibrosis. Faseb. J. 2012, 26:2338-2350.
229. Zhang Z.Y. Mechanistic studies on protein tyrosine phosphatases. Prog. Nucleic acid Res. Mol. Biol. 2003, 73:171-220.
230. Zheng H., Li S., Hsu P., Qu C.K. Induction of a tumor-associated activating mutation in protein tyrosine phosphatase Ptpn11 (Shp2) enhances mitochondrial metabolism, leading to oxidative stress and senescence. J. Biol. Chem. 2013, 288:25727-25738.
231. Zhou R.P., Deng M.T., Chen L.Y., Fang N., Du C., Chen L.P., et al. Shp2 regulates chlorogenic acid-induced proliferation and adipogenic differentiation of bone marrow-derived mesenchymal stem cells in adipogenesis. Mol. Med. Rep. 2015, 11:4489-4495.
232. Zhu H.H., Ji K., Alderson N., He Z., Li S., Liu W., et al. Kit-Shp2-Kit signaling acts to maintain a functional hematopoietic stem and progenitor cell pool. Blood 2011, 117:5350-5361.
233. Zito C.I., Qin H., Blenis J., Bennett A.M. SHP-2 regulates cell growth by controlling the mTOR/S6 kinase 1 pathway. J. Biol. Chem. 2007, 282:6946-6953.