| Structural highlights
Disease
PTN11_HUMAN Defects in PTPN11 are the cause of LEOPARD syndrome type 1 (LEOPARD1) [MIM:151100. It is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness.[1] [2] [3] [4] [5] [6] [7] Defects in PTPN11 are the cause of Noonan syndrome type 1 (NS1) [MIM:163950. Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. Some patients with Noonan syndrome type 1 develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villomoduolar synovitis (PVNS) when occurring in the jaw or joints. Note=Mutations in PTPN11 account for more than 50% of the cases. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS1 inheritance is autosomal dominant.[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] Defects in PTPN11 are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. It is characterized by leukocytosis with tissue infiltration and in vitro hypersensitivity of myeloid progenitors to granulocyte-macrophage colony stimulating factor.[20] Defects in PTPN11 are a cause of metachondromatosis (MC) [MIM:156250. It is a skeletal disorder with radiologic fetarures of both multiple exostoses and Ollier disease, characterized by the presence of multiple enchondromas and osteochondroma-like lesions.[21]
Function
PTN11_HUMAN Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. Dephosphorylates ROCK2 at Tyr-722 resulting in stimulatation of its RhoA binding activity.[22] [23] [24]
Publication Abstract from PubMed
SHP2 is the first oncogenic tyrosine phosphatase encoded by PTPN11, which plays a significant regulatory role in cancer and inflammation-related diseases. Although SHP2 allosteric inhibitors have been used in phase I/II clinical trials for solid tumors, whether SHP2 inhibition alleviates psoriasis remains unclear. Here we expressed and purified SHP2 related proteins, and established an enzyme activity screening system for different conformations of SHP2. We launched an iterative medicinal chemistry program and identified the lead compound, TK-453. Importantly, TK-453 possessed stronger affinity with SHP2 than SHP099, evidenced by the cocrystal structure of SHP2/TK-453, revealing that the additional aryl-S-aryl bridge in TK-453 induces a 1.8 A shift of the dichlorophenyl ring and an approximate 20 degrees deviation of the pyrazine ring plane relative to SHP099. Furthermore, TK-453 significantly ameliorated imiquimod-triggered skin inflammation in mice via inhibition of the IL-23/Th17 axis, proving that SHP2 is a potential therapeutic target for psoriasis.
SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis.,Wang M, Li T, Ouyang Z, Tang K, Zhu Y, Song C, Sun H, Yu B, Ji X, Sun Y iScience. 2022 Mar 1;25(4):104009. doi: 10.1016/j.isci.2022.104009. eCollection, 2022 Apr 15. PMID:35310939[25]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002 Aug;71(2):389-94. Epub 2002 Jun 7. PMID:12058348 doi:S0002-9297(07)60483-2
- ↑ Conti E, Dottorini T, Sarkozy A, Tiller GE, Esposito G, Pizzuti A, Dallapiccola B. A novel PTPN11 mutation in LEOPARD syndrome. Hum Mutat. 2003 Jun;21(6):654. PMID:14961557 doi:10.1002/humu.9149
- ↑ Yoshida R, Nagai T, Hasegawa T, Kinoshita E, Tanaka T, Ogata T. Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. Am J Med Genet A. 2004 Nov 1;130A(4):432-4. PMID:15389709 doi:10.1002/ajmg.a.30281
- ↑ Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, Boute O, Gaillard D, Lacombe D, Layet V, Marlin S, Mortier G, Toutain A, Beylot C, Baumann C, Verloes A, Cave H. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet. 2004 Nov;41(11):e117. PMID:15520399 doi:10.1136/jmg.2004.021451
- ↑ Sarkozy A, Conti E, Digilio MC, Marino B, Morini E, Pacileo G, Wilson M, Calabro R, Pizzuti A, Dallapiccola B. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004 May;41(5):e68. PMID:15121796
- ↑ Kalidas K, Shaw AC, Crosby AH, Newbury-Ecob R, Greenhalgh L, Temple IK, Law C, Patel A, Patton MA, Jeffery S. Genetic heterogeneity in LEOPARD syndrome: two families with no mutations in PTPN11. J Hum Genet. 2005;50(1):21-5. Epub 2004 Dec 10. PMID:15690106 doi:10.1007/s10038-004-0212-x
- ↑ 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 Mar;28(3):123-5. PMID:16679933 doi:10.1097/01.mph.0000199590.21797.0b
- ↑ Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID:11704759 doi:10.1038/ng772
- ↑ Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. Epub 2002 May 1. PMID:11992261 doi:10.1086/340847
- ↑ Maheshwari M, Belmont J, Fernbach S, Ho T, Molinari L, Yakub I, Yu F, Combes A, Towbin J, Craigen WJ, Gibbs R. PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13. Hum Mutat. 2002 Oct;20(4):298-304. PMID:12325025 doi:10.1002/humu.10129
- ↑ Kosaki K, Suzuki T, Muroya K, Hasegawa T, Sato S, Matsuo N, Kosaki R, Nagai T, Hasegawa Y, Ogata T. PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. J Clin Endocrinol Metab. 2002 Aug;87(8):3529-33. PMID:12161469
- ↑ Schollen E, Matthijs G, Gewillig M, Fryns JP, Legius E. PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning. Eur J Hum Genet. 2003 Jan;11(1):85-8. PMID:12529711 doi:10.1038/sj.ejhg.5200915
- ↑ Musante L, Kehl HG, Majewski F, Meinecke P, Schweiger S, Gillessen-Kaesbach G, Wieczorek D, Hinkel GK, Tinschert S, Hoeltzenbein M, Ropers HH, Kalscheuer VM. Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. Eur J Hum Genet. 2003 Feb;11(2):201-6. PMID:12634870 doi:10.1038/sj.ejhg.5200935
- ↑ Kondoh T, Ishii E, Aoki Y, Shimizu T, Zaitsu M, Matsubara Y, Moriuchi H. Noonan syndrome with leukaemoid reaction and overproduction of catecholamines: a case report. Eur J Pediatr. 2003 Jul;162(7-8):548-9. Epub 2003 May 9. PMID:12739139 doi:10.1007/s00431-003-1227-6
- ↑ Sarkozy A, Conti E, Seripa D, Digilio MC, Grifone N, Tandoi C, Fazio VM, Di Ciommo V, Marino B, Pizzuti A, Dallapiccola B. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet. 2003 Sep;40(9):704-8. PMID:12960218
- ↑ Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003 Jun;34(2):148-50. PMID:12717436 doi:10.1038/ng1156
- ↑ Bertola DR, Pereira AC, de Oliveira PS, Kim CA, Krieger JE. Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation. Am J Med Genet A. 2004 Nov 1;130A(4):378-83. PMID:15384080 doi:10.1002/ajmg.a.30270
- ↑ Bertola DR, Pereira AC, Passetti F, de Oliveira PS, Messiaen L, Gelb BD, Kim CA, Krieger JE. Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient. Am J Med Genet A. 2005 Jul 30;136(3):242-5. PMID:15948193 doi:10.1002/ajmg.a.30813
- ↑ Ko JM, Kim JM, Kim GH, Yoo HW. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53(11-12):999-1006. doi: 10.1007/s10038-008-0343-6. Epub 2008, Nov 20. PMID:19020799 doi:10.1007/s10038-008-0343-6
- ↑ Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003 Jun;34(2):148-50. PMID:12717436 doi:10.1038/ng1156
- ↑ Sobreira NL, Cirulli ET, Avramopoulos D, Wohler E, Oswald GL, Stevens EL, Ge D, Shianna KV, Smith JP, Maia JM, Gumbs CE, Pevsner J, Thomas G, Valle D, Hoover-Fong JE, Goldstein DB. Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet. 2010 Jun 17;6(6):e1000991. doi: 10.1371/journal.pgen.1000991. PMID:20577567 doi:10.1371/journal.pgen.1000991
- ↑ Miao H, Burnett E, Kinch M, Simon E, Wang B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2000 Feb;2(2):62-9. PMID:10655584 doi:10.1038/35000008
- ↑ Jakob S, Schroeder P, Lukosz M, Buchner N, Spyridopoulos I, Altschmied J, Haendeler J. Nuclear protein tyrosine phosphatase Shp-2 is one important negative regulator of nuclear export of telomerase reverse transcriptase. J Biol Chem. 2008 Nov 28;283(48):33155-61. doi: 10.1074/jbc.M805138200. Epub 2008, Oct 1. PMID:18829466 doi:10.1074/jbc.M805138200
- ↑ Lee HH, Chang ZF. Regulation of RhoA-dependent ROCKII activation by Shp2. J Cell Biol. 2008 Jun 16;181(6):999-1012. doi: 10.1083/jcb.200710187. PMID:18559669 doi:10.1083/jcb.200710187
- ↑ Wang M, Li T, Ouyang Z, Tang K, Zhu Y, Song C, Sun H, Yu B, Ji X, Sun Y. SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis. iScience. 2022 Mar 1;25(4):104009. doi: 10.1016/j.isci.2022.104009. eCollection, 2022 Apr 15. PMID:35310939 doi:https://dx.doi.org/10.1016/j.isci.2022.104009
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