PTPN11

PTPN11
PDBに登録されている構造
PDB	オルソログ検索: RCSB PDBe PDBj
PDBのIDコード一覧
	2SHP, 3B7O, 3MOW, 3O5X, 3TKZ, 3TL0, 4DGP, 4DGX, 4GWF, 4H1O, 4JE4, 4JEG, 3ZM0, 3ZM1, 3ZM2, 3ZM3, 4H34, 4JMG, 4NWF, 4NWG, 4OHD, 4OHE, 4OHH, 4OHI, 4OHL, 4PVG, 4RDD, 4QSY, 5DF6, 5IBS, 5EHP, 5EHR, 5I6V, 5IBM
識別子
記号	PTPN11, BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2, protein tyrosine phosphatase, non-receptor type 11, protein tyrosine phosphatase non-receptor type 11
外部ID	OMIM: 176876 MGI: 99511 HomoloGene: 2122 GeneCards: PTPN11
遺伝子の位置 (ヒト)
染色体	12番染色体 (ヒト)
終点	112,509,918 bp
遺伝子の位置 (マウス)
染色体	5番染色体 (マウス)
終点	121,329,460 bp
RNA発現パターン
	さらなる参照発現データ
遺伝子オントロジー
分子機能	• phospholipase binding; • phosphoprotein phosphatase activity; • insulin receptor binding; • ホスファターゼ活性; • receptor tyrosine kinase binding; • peptide hormone receptor binding; • 血漿タンパク結合; • non-membrane spanning protein tyrosine phosphatase activity; • 加水分解酵素活性; • phosphatidylinositol-4,5-bisphosphate 3-kinase activity; • 1-phosphatidylinositol-3-kinase activity; • cell adhesion molecule binding; • protein tyrosine phosphatase activity; • phosphotyrosine residue binding; • protein domain specific binding; • D1 dopamine receptor binding; • insulin receptor substrate binding; • protein tyrosine kinase binding; • プロテインキナーゼ結合;
細胞の構成要素	• 細胞質; • 細胞質基質; • ミトコンドリア; • 細胞核; • 核質; • 高分子複合体;
生物学的プロセス	• 脱リン酸化; • megakaryocyte development; • positive regulation of signal transduction; • negative regulation of insulin secretion; • regulation of cell adhesion mediated by integrin; • atrioventricular canal development; • intestinal epithelial cell migration; • organ growth; • epidermal growth factor receptor signaling pathway; • negative regulation of growth hormone secretion; • axonogenesis; • glucose homeostasis; • regulation of protein export from nucleus; • multicellular organism growth; • regulation of multicellular organism growth; • 脂質代謝; • ephrin receptor signaling pathway; • abortive mitotic cell cycle; • DNA damage checkpoint signaling; • protein dephosphorylation; • T cell costimulation; • 血小板形成; • microvillus organization; • positive regulation of mitotic cell cycle; • 性器発生; • platelet activation; • fibroblast growth factor receptor signaling pathway; • 心臓発生; • 脳発生; • regulation of type I interferon-mediated signaling pathway; • hormone-mediated signaling pathway; • integrin-mediated signaling pathway; • Bergmann glial cell differentiation; • homeostasis of number of cells within a tissue; • inner ear development; • platelet-derived growth factor receptor signaling pathway; • negative regulation of cortisol secretion; • peptidyl-tyrosine dephosphorylation; • ERBB signaling pathway; • negative regulation of hormone secretion; • triglyceride metabolic process; • ホルモン代謝プロセス; • positive regulation of hormone secretion; • negative regulation of cell adhesion mediated by integrin; • regulation of protein-containing complex assembly; • face morphogenesis; • cerebellar cortex formation; • leukocyte migration; • multicellular organismal reproductive process; • phosphatidylinositol phosphate biosynthetic process; • neurotrophin TRK receptor signaling pathway; • phosphatidylinositol-3-phosphate biosynthetic process; • 軸索誘導; • positive regulation of ERK1 and ERK2 cascade; • cellular response to epidermal growth factor stimulus; • positive regulation of protein kinase B signaling; • サイトカイン媒介シグナル伝達経路; • interleukin-6-mediated signaling pathway; • cellular response to cytokine stimulus; • cellular response to mechanical stimulus; • positive regulation of interferon-beta production; • positive regulation of interleukin-6 production; • positive regulation of tumor necrosis factor production; • positive regulation of glucose import; • positive regulation of insulin receptor signaling pathway;
	出典:Amigo / QuickGO
オルソログ
	5781
	19247
	ENSG00000179295
	ENSMUSG00000043733
	Q06124,H0YF12
	P35235
	NM_002834; NM_080601; NM_001330437; NM_001374625; NM_018508
	NM_001109992; NM_011202
	NP_001317366; NP_002825; NP_542168; NP_001361554
	NP_001103462; NP_035332
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

PTPN11（Protein-tyrosine phosphatase non-receptor type 11）またはSHP2（Src homology region 2 domain-containing phosphatase 2）は、ヒトではPTPN11遺伝子によってコードされている酵素である。PTP-1D（protein-tyrosine phosphatase 1D）、PTP-2C（protein-tyrosine phosphatase 2C）としても知られ、プロテインチロシンホスファターゼ（PTP）である^[5]^[6]。

PTPN11はPTPファミリーに属する。PTPは、細胞増殖、細胞分化、有糸分裂サイクル、発がん性形質転換など、さまざまな細胞過程を調節するシグナル伝達分子であることが知られている。PTPN11は2つのタンデムなSH2ドメインを含んでおり、リン酸化チロシン結合ドメインとして基質との相互作用を媒介する。大部分の組織で広く発現しており、有糸分裂の活性化、代謝の制御、転写の調節、細胞遊走など、幅広い細胞機能に重要なシグナル伝達を調節する役割を果たす。この遺伝子の変異はヌーナン症候群や急性骨髄性白血病の原因となる^[7]。

構造と機能

SHP2は、パラログであるSHP1（PTPN6（英語版））と同じく、N末端の2つのタンデムなSH2ドメインにPTPドメインが続くというドメイン構造をしている。不活性状態では、N末端のSH2ドメインがPTPドメインに結合して基質が活性部位へアクセスすることを防いでおり、自己阻害状態となっている。標的のリン酸化チロシン残基への結合に伴ってN末端のSH2ドメインはPTPドメインから解離し、自己阻害状態を解除することによって酵素を活性化する。

PTPN11と関係した遺伝子疾患

PTPN11遺伝子座のミスセンス変異はヌーナン症候群とLEOPARD症候群の双方と関係している。

また、メタコンドロマトーシスとも関係している^[8]。

ヌーナン症候群

ヌーナン症候群の症例におけるPTPN11の変異は遺伝子のコーディング領域全体にわたって広く分布しているが、すべて過剰活性化型や調節異常型のSHP2タンパク質の産生をもたらすようである。これらの変異の大部分は、自己阻害型コンフォメーションの維持に必要な、N末端のSH2ドメインと触媒コアとの相互作用面を破壊するものである^[9]。

LEOPARD症候群

LEPPARD症候群を引き起こす変異は酵素の触媒コアに影響を与える領域に限定されており、触媒活性が損なわれたSHP2タンパク質が産生される^[10]。生化学的には反対の特徴を生じさせる変異が、ヌーナン症候群とLEPPARD症候群という類似した遺伝子疾患を引き起こす理由は今のところ明らかではない。

PTPN11と関係したがん

ヌーナン症候群を引き起こすPTPN11の変異の一部では、若年性骨髄単球性白血病の高い発病率も観察される。SHP2の活性化型変異は、神経芽細胞腫、悪性黒色腫、急性骨髄性白血病、乳がん、肺がん、大腸がんでも検出されている^[11]。近年では、NPM1変異型の急性骨髄性白血病患者のコホート研究において、比較的高いPTPN11変異の保有率（24%）がみられることが次世代シーケンシングによって検出されている^[12]。しかし、こうした関係が予後に与える重要性は明確にはされていない。こうしたデータはSHP2ががん原遺伝子である可能性を示唆している。一方で、PTPN11/SHP2が腫瘍形成の促進因子と抑制因子のいずれとしても作用しうることが報告されている^[13]。老齢マウスモデルでは、肝細胞特異的なPTPN11/SHP2の欠失はSTAT3経路を介した炎症性シグナル伝達と肝細胞の炎症/壊死を促進し、結節性再生性過形成（英語版）と腫瘍形成を引き起こす。また、ヒトの肝細胞がん試料の一部ではPTPN11/SHP2の発現の低下が検出された^[13]。

ピロリ菌CagAタンパク質

ピロリ菌Helicobacter pyloriは胃がんと関係しているが、その一部はピロリ菌の病原性因子であるCagA（英語版）とSHP2との相互作用によるものであると考えられている^[14]。CagAはピロリ菌によって胃上皮に挿入されるタンパク質である。Srcによるリン酸化によって活性化されると、CagAはSHP2に結合し、アロステリックにSHP2の活性化を引き起こす。その結果、形態学的変化と異常な有糸分裂促進シグナルが引き起こされ、持続的な活性によって宿主細胞のアポトーシスが引き起こされることもある。萎縮性胃炎、消化性潰瘍、胃がんの発症におけるcagA陽性ピロリ菌の役割が疫学的研究によって示されている^[15]。

相互作用

PRPN11は次に挙げる因子と相互作用することが示されている。

CagA（英語版）^[14]
CBL^[16]
KIT^[17]^[18]
CD31^[19]^[20]^[21]^[22]
CEACAM1（英語版）^[23]
EGFR^[24]^[25]
Erk^[26]^[27]
FRS2（英語版）^[28]^[29]^[30]
GAB1（英語版）^[31]^[32]
GAB2（英語版）^[33]^[34]^[35]^[36]
GAB3（英語版）^[37]
gp130（英語版）^[38]^[39]^[40]
GRB2^[30]^[41]^[42]^[43]^[44]^[45]^[46]^[47]^[48]
GHR^[49]^[50]
HOXA10（英語版）^[51]
INSR^[52]^[53]
IGF1R^[54]^[55]
IRS1^[56]^[57]
JAK1（英語版）^[38]^[41]
JAK2^[41]^[58]^[59]
LAIR1（英語版）^[60]^[61]
LRP1（英語版）^[62]
PDGFRB（英語版）^[63]^[64]
PI3K → Akt^[26]
PLCG2（英語版）^[33]
PTK2B（英語版）^[65]
Ras^[26]^[27]
SLAMF1（英語版）^[66]^[67]
SOCS3（英語版）^[38]
SOS1（英語版）^[30]^[68]
STAT3^[13]
STAT5A^[69]^[70]
STAT5B^[69]

出典

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000179295 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000043733 - Ensembl, May 2017
^ Human PubMed Reference:
^ Mouse PubMed Reference:
^ “Mapping a gene for Noonan syndrome to the long arm of chromosome 12”. Nat. Genet. 8 (4): 357–60. (December 1994). doi:10.1038/ng1294-357. PMID 7894486.
^ “Identification of a human Src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew”. Proc. Natl. Acad. Sci. U.S.A. 89 (23): 11239–43. (December 1992). doi:10.1073/pnas.89.23.11239. PMC 50525. PMID 1280823.
^ “Entrez Gene: PTPN11 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1)”. 2020年9月30日閲覧。
^ “Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene”. PLoS Genet. 6 (6): e1000991. (June 2010). doi:10.1371/journal.pgen.1000991. PMC 2887469. PMID 20577567.
^ “Germline gain-of-function mutations in SOS1 cause Noonan syndrome”. Nat. Genet. 39 (1): 70–4. (January 2007). doi:10.1038/ng1926. PMID 17143285.
^ “PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects”. J. Biol. Chem. 281 (10): 6785–92. (March 2006). doi:10.1074/jbc.M513068200. PMID 16377799.
^ “Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia”. Cancer Res. 64 (24): 8816–20. (December 2004). doi:10.1158/0008-5472.CAN-04-1923. PMID 15604238.
^ “High NPM1 mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML”. Blood 131 (25): 2816–2825. (May 2018). doi:10.1182/blood-2018-01-828467. PMC 6265642. PMID 29724895.
^ ^a ^b ^c “Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis”. Cancer Cell 19 (5): 629–39. (May 2011). doi:10.1016/j.ccr.2011.03.023. PMC 3098128. PMID 21575863.
^ ^a ^b “Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis”. Cancer Science 96 (12): 835–843. (2005). doi:10.1111/j.1349-7006.2005.00130.x. PMID 16367902.
^ “Oncogenic mechanisms of the Helicobacter pylori CagA protein”. Nature Reviews Cancer 4 (9): 688–94. (September 2004). doi:10.1038/nrc1433. PMID 15343275.
^ “c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130”. Mol. Cell. Biol. 28 (15): 4805–18. (Aug 2008). doi:10.1128/MCB.01784-07. PMC 2493370. PMID 18519587.
^ “The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells”. J. Biol. Chem. 269 (40): 25206–11. (October 1994). PMID 7523381.
^ “SHP-1 binds and negatively modulates the c-Kit receptor by interaction with tyrosine 569 in the c-Kit juxtamembrane domain”. Mol. Cell. Biol. 18 (4): 2089–99. (April 1998). doi:10.1128/MCB.18.4.2089. PMC 121439. PMID 9528781.
^ “Platelet-endothelial cell adhesion molecule-1 (CD31), a scaffolding molecule for selected catenin family members whose binding is mediated by different tyrosine and serine/threonine phosphorylation”. J. Biol. Chem. 275 (28): 21435–43. (July 2000). doi:10.1074/jbc.M001857200. PMID 10801826.
^ “Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31”. FEBS Lett. 450 (1–2): 77–83. (April 1999). doi:10.1016/S0014-5793(99)00446-9. PMID 10350061.
^ “Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates”. J. Biol. Chem. 273 (43): 28332–40. (October 1998). doi:10.1074/jbc.273.43.28332. PMID 9774457.
^ “The protein-tyrosine phosphatase SHP-2 binds platelet/endothelial cell adhesion molecule-1 (PECAM-1) and forms a distinct signaling complex during platelet aggregation. Evidence for a mechanistic link between PECAM-1- and integrin-mediated cellular signaling”. J. Biol. Chem. 272 (11): 6986–93. (March 1997). doi:10.1074/jbc.272.11.6986. PMID 9054388.
^ “The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells”. J. Biol. Chem. 274 (1): 335–44. (Jan 1999). doi:10.1074/jbc.274.1.335. PMID 9867848.
^ “Phosphotyrosine interactome of the ErbB-receptor kinase family”. Mol. Syst. Biol. 1 (1): E1–E13. (2005). doi:10.1038/msb4100012. PMC 1681463. PMID 16729043.
^ “Association of SH2 domain protein tyrosine phosphatases with the epidermal growth factor receptor in human tumor cells. Phosphatidic acid activates receptor dephosphorylation by PTP1C”. J. Biol. Chem. 270 (36): 21277–84. (Sep 1995). doi:10.1074/jbc.270.36.21277. PMID 7673163.
^ ^a ^b ^c L.A. Lai; C. Zhao; E.E. Zhang; G.S. Feng (2004). “14 The Shp-2 tyrosine phosphatase”. In Joaquín Ariño; Denis Alexander. Protein phosphatases. Springer. pp. 275–299. ISBN 978-3-540-20560-9
^ ^a ^b “The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling”. Trends in Biochemical Sciences 28 (6): 284–293. (June 2003). doi:10.1016/S0968-0004(03)00091-4. ISSN 0968-0004. PMID 12826400.
^ “Potential involvement of FRS2 in insulin signaling”. Endocrinology 141 (2): 621–8. (Feb 2000). doi:10.1210/endo.141.2.7298. PMID 10650943.
^ “Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction”. Oncogene 20 (16): 1929–38. (Apr 2001). doi:10.1038/sj.onc.1204290. PMID 11360177.
^ ^a ^b ^c “Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation”. Mol. Cell. Biol. 18 (7): 3966–73. (Jul 1998). doi:10.1128/MCB.18.7.3966. PMC 108981. PMID 9632781.
^ “Protein kinase C-alpha and protein kinase C-epsilon are required for Grb2-associated binder-1 tyrosine phosphorylation in response to platelet-derived growth factor”. J. Biol. Chem. 277 (26): 23216–22. (Jun 2002). doi:10.1074/jbc.M200605200. PMID 11940581.
^ “Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules”. Mol. Endocrinol. 12 (7): 914–23. (Jul 1998). doi:10.1210/mend.12.7.0141. PMID 9658397.
^ ^a ^b “Phosphatidylinositol 3-kinase regulates glycosylphosphatidylinositol hydrolysis through PLC-gamma(2) activation in erythropoietin-stimulated cells”. Cell. Signal. 14 (10): 869–78. (October 2002). doi:10.1016/S0898-6568(02)00036-0. PMID 12135708.
^ “PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2”. EMBO J. 21 (1–2): 72–82. (January 2002). doi:10.1093/emboj/21.1.72. PMC 125816. PMID 11782427.
^ “Gab2, a new pleckstrin homology domain-containing adapter protein, acts to uncouple signaling from ERK kinase to Elk-1”. J. Biol. Chem. 274 (28): 19649–54. (July 1999). doi:10.1074/jbc.274.28.19649. PMID 10391903.
^ “A yeast two-hybrid study of human p97/Gab2 interactions with its SH2 domain-containing binding partners”. FEBS Lett. 495 (3): 148–53. (April 2001). doi:10.1016/S0014-5793(01)02373-0. PMID 11334882.
^ Wolf, I.; Jenkins, B. J.; Liu, Y.; Seiffert, M.; Custodio, J. M.; Young, P.; Rohrschneider, L. R. (2002). “Gab3, a New DOS/Gab Family Member, Facilitates Macrophage Differentiation”. Molecular and Cellular Biology 22 (1): 231–244. doi:10.1128/MCB.22.1.231-244.2002. ISSN 0270-7306. PMC 134230. PMID 11739737. "and associates transiently with the SH2 domain-containing proteins p85 and SHP2"
^ ^a ^b ^c “SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130”. J. Biol. Chem. 278 (1): 661–71. (January 2003). doi:10.1074/jbc.M210552200. PMID 12403768.
^ “Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: structural receptor requirements for signal attenuation”. Journal of Immunology 165 (5): 2535–43. (Sep 2000). doi:10.4049/jimmunol.165.5.2535. PMID 10946280.
^ “Transmembrane domain of gp130 contributes to intracellular signal transduction in hepatic cells”. J. Biol. Chem. 272 (49): 30741–7. (Dec 1997). doi:10.1074/jbc.272.49.30741. PMID 9388212.
^ ^a ^b ^c “Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases”. J. Biol. Chem. 272 (2): 1032–7. (January 1997). doi:10.1074/jbc.272.2.1032. PMID 8995399.
^ “Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk”. J. Biol. Chem. 275 (23): 17263–8. (Jun 2000). doi:10.1074/jbc.M000689200. PMID 10747947.
^ “Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras”. Proc. Natl. Acad. Sci. U.S.A. 91 (15): 7335–9. (Jul 1994). doi:10.1073/pnas.91.15.7335. PMC 44394. PMID 8041791.
^ “Direct binding of Shc, Grb2, SHP-2 and p40 to the murine granulocyte colony-stimulating factor receptor”. Biochim. Biophys. Acta 1448 (1): 70–6. (Nov 1998). doi:10.1016/S0167-4889(98)00120-7. PMID 9824671.
^ “Induced direct binding of the adapter protein Nck to the GTPase-activating protein-associated protein p62 by epidermal growth factor”. Oncogene 15 (15): 1823–32. (Oct 1997). doi:10.1038/sj.onc.1201351. PMID 9362449.
^ “Fyn kinase-directed activation of SH2 domain-containing protein-tyrosine phosphatase SHP-2 by Gi protein-coupled receptors in Madin-Darby canine kidney cells”. J. Biol. Chem. 274 (18): 12401–7. (Apr 1999). doi:10.1074/jbc.274.18.12401. PMID 10212213.
^ “Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells”. J. Leukoc. Biol. 65 (3): 372–80. (Mar 1999). doi:10.1002/jlb.65.3.372. PMID 10080542.
^ “Epidermal growth factor induces coupling of protein-tyrosine phosphatase 1D to GRB2 via the COOH-terminal SH3 domain of GRB2”. J. Biol. Chem. 271 (35): 20981–4. (Aug 1996). doi:10.1074/jbc.271.35.20981. PMID 8702859.
^ “Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B”. Mol. Endocrinol. 14 (9): 1338–50. (September 2000). doi:10.1210/me.14.9.1338. PMID 10976913.
^ “Grb10 identified as a potential regulator of growth hormone (GH) signaling by cloning of GH receptor target proteins”. J. Biol. Chem. 273 (26): 15906–12. (June 1998). doi:10.1074/jbc.273.26.15906. PMID 9632636.
^ “Constitutively active SHP2 cooperates with HoxA10 overexpression to induce acute myeloid leukemia.”. J Biol Chem 284 (4): 2549–67. (Jan 2009). doi:10.1074/jbc.M804704200. PMC 2629090. PMID 19022774.
^ “Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro”. Biochem. Biophys. Res. Commun. 199 (2): 780–5. (Mar 1994). doi:10.1006/bbrc.1994.1297. PMID 8135823.
^ “Adapter function of protein-tyrosine phosphatase 1D in insulin receptor/insulin receptor substrate-1 interaction”. J. Biol. Chem. 270 (49): 29189–93. (Dec 1995). doi:10.1074/jbc.270.49.29189. PMID 7493946.
^ “Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility”. Mol. Cell. Biol. 19 (4): 3125–35. (Apr 1999). doi:10.1128/mcb.19.4.3125. PMC 84106. PMID 10082579.
^ “Localization of the insulin-like growth factor I receptor binding sites for the SH2 domain proteins p85, Syp, and GTPase activating protein”. J. Biol. Chem. 270 (32): 19151–7. (Aug 1995). doi:10.1074/jbc.270.32.19151. PMID 7642582.
^ “The insulin receptor substrate 1 associates with the SH2-containing phosphotyrosine phosphatase Syp”. J. Biol. Chem. 268 (16): 11479–81. (Jun 1993). PMID 8505282.
^ “The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling”. J. Biol. Chem. 273 (41): 26908–14. (Oct 1998). doi:10.1074/jbc.273.41.26908. PMID 9756938.
^ “Tyrosine 425 within the activated erythropoietin receptor binds Syp, reduces the erythropoietin required for Syp tyrosine phosphorylation, and promotes mitogenesis”. Blood 87 (11): 4495–501. (June 1996). doi:10.1182/blood.V87.11.4495.bloodjournal87114495. PMID 8639815.
^ “SHPTP2 serves adapter protein linking between Janus kinase 2 and insulin receptor substrates”. Biochem. Biophys. Res. Commun. 228 (1): 122–7. (November 1996). doi:10.1006/bbrc.1996.1626. PMID 8912646.
^ “FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells”. Journal of Immunology 165 (3): 1197–209. (Aug 2000). doi:10.4049/jimmunol.165.3.1197. PMID 10903717.
^ “LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes”. Immunity 7 (2): 283–90. (Aug 1997). doi:10.1016/S1074-7613(00)80530-0. PMID 9285412.
^ “Structural and functional consequences of tyrosine phosphorylation in the LRP1 cytoplasmic domain”. J. Biol. Chem. 283 (23): 15656–64. (June 2008). doi:10.1074/jbc.M709514200. PMC 2414285. PMID 18381291.
^ “Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1”. J. Cell Biol. 152 (2): 325–34. (Jan 2001). doi:10.1083/jcb.152.2.325. PMC 2199605. PMID 11266449.
^ “Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor”. J. Biol. Chem. 268 (29): 21478–81. (Oct 1993). PMID 7691811.
^ “SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells”. J. Biol. Chem. 275 (36): 27845–50. (September 2000). doi:10.1074/jbc.M003428200. PMID 10880513.
^ “Molecular dissection of the signaling and costimulatory functions of CD150 (SLAM): CD150/SAP binding and CD150-mediated costimulation”. Blood 99 (3): 957–65. (Feb 2000). doi:10.1182/blood.V99.3.957. PMID 11806999.
^ “Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells”. EMBO J. 20 (21): 5840–52. (Nov 2001). doi:10.1093/emboj/20.21.5840. PMC 125701. PMID 11689425.
^ “Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells”. Biochem. Biophys. Res. Commun. 239 (2): 412–7. (Oct 1997). doi:10.1006/bbrc.1997.7480. PMID 9344843.
^ ^a ^b “Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation”. J. Biol. Chem. 275 (1): 599–604. (Jan 2000). doi:10.1074/jbc.275.1.599. PMID 10617656.
^ “Prolactin induces SHP-2 association with Stat5, nuclear translocation, and binding to the beta-casein gene promoter in mammary cells”. J. Biol. Chem. 277 (34): 31107–14. (Aug 2002). doi:10.1074/jbc.M200156200. PMID 12060651.

外部リンク

GeneReviews/NCBI/NIH/UW entry on Noonan syndrome

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000179295 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000043733 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

[pmid7894486-5] “Mapping a gene for Noonan syndrome to the long arm of chromosome 12”. Nat. Genet. 8 (4): 357–60. (December 1994). doi:10.1038/ng1294-357. PMID 7894486.

[pmid1280823-6] “Identification of a human Src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew”. Proc. Natl. Acad. Sci. U.S.A. 89 (23): 11239–43. (December 1992). doi:10.1073/pnas.89.23.11239. PMC 50525. PMID 1280823.

[:0-7] “Entrez Gene: PTPN11 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1)”. 2020年9月30日閲覧。

[pmid20577567-8] “Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene”. PLoS Genet. 6 (6): e1000991. (June 2010). doi:10.1371/journal.pgen.1000991. PMC 2887469. PMID 20577567.

[pmid17143285-9] “Germline gain-of-function mutations in SOS1 cause Noonan syndrome”. Nat. Genet. 39 (1): 70–4. (January 2007). doi:10.1038/ng1926. PMID 17143285.

[pmid16377799-10] “PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects”. J. Biol. Chem. 281 (10): 6785–92. (March 2006). doi:10.1074/jbc.M513068200. PMID 16377799.

[pmid15604238-11] “Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia”. Cancer Res. 64 (24): 8816–20. (December 2004). doi:10.1158/0008-5472.CAN-04-1923. PMID 15604238.

[:1-12] “High NPM1 mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML”. Blood 131 (25): 2816–2825. (May 2018). doi:10.1182/blood-2018-01-828467. PMC 6265642. PMID 29724895.

[Gen-Sheng_Feng-13] “Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis”. Cancer Cell 19 (5): 629–39. (May 2011). doi:10.1016/j.ccr.2011.03.023. PMC 3098128. PMID 21575863.

[pmid16367902-14] “Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis”. Cancer Science 96 (12): 835–843. (2005). doi:10.1111/j.1349-7006.2005.00130.x. PMID 16367902.

[pmid15343275-15] “Oncogenic mechanisms of the Helicobacter pylori CagA protein”. Nature Reviews Cancer 4 (9): 688–94. (September 2004). doi:10.1038/nrc1433. PMID 15343275.

[pmid18519587-16] “c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130”. Mol. Cell. Biol. 28 (15): 4805–18. (Aug 2008). doi:10.1128/MCB.01784-07. PMC 2493370. PMID 18519587.

[pmid7523381-17] “The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells”. J. Biol. Chem. 269 (40): 25206–11. (October 1994). PMID 7523381.

[pmid9528781-18] “SHP-1 binds and negatively modulates the c-Kit receptor by interaction with tyrosine 569 in the c-Kit juxtamembrane domain”. Mol. Cell. Biol. 18 (4): 2089–99. (April 1998). doi:10.1128/MCB.18.4.2089. PMC 121439. PMID 9528781.

[pmid10801826-19] “Platelet-endothelial cell adhesion molecule-1 (CD31), a scaffolding molecule for selected catenin family members whose binding is mediated by different tyrosine and serine/threonine phosphorylation”. J. Biol. Chem. 275 (28): 21435–43. (July 2000). doi:10.1074/jbc.M001857200. PMID 10801826.

[pmid10350061-20] “Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31”. FEBS Lett. 450 (1–2): 77–83. (April 1999). doi:10.1016/S0014-5793(99)00446-9. PMID 10350061.

[pmid9774457-21] “Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates”. J. Biol. Chem. 273 (43): 28332–40. (October 1998). doi:10.1074/jbc.273.43.28332. PMID 9774457.

[pmid9054388-22] “The protein-tyrosine phosphatase SHP-2 binds platelet/endothelial cell adhesion molecule-1 (PECAM-1) and forms a distinct signaling complex during platelet aggregation. Evidence for a mechanistic link between PECAM-1- and integrin-mediated cellular signaling”. J. Biol. Chem. 272 (11): 6986–93. (March 1997). doi:10.1074/jbc.272.11.6986. PMID 9054388.

[pmid9867848-23] “The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells”. J. Biol. Chem. 274 (1): 335–44. (Jan 1999). doi:10.1074/jbc.274.1.335. PMID 9867848.

[pmid16729043-24] “Phosphotyrosine interactome of the ErbB-receptor kinase family”. Mol. Syst. Biol. 1 (1): E1–E13. (2005). doi:10.1038/msb4100012. PMC 1681463. PMID 16729043.

[pmid7673163-25] “Association of SH2 domain protein tyrosine phosphatases with the epidermal growth factor receptor in human tumor cells. Phosphatidic acid activates receptor dephosphorylation by PTP1C”. J. Biol. Chem. 270 (36): 21277–84. (Sep 1995). doi:10.1074/jbc.270.36.21277. PMID 7673163.

[Shp2_Erk_PI3K-26] L.A. Lai; C. Zhao; E.E. Zhang; G.S. Feng (2004). “14 The Shp-2 tyrosine phosphatase”. In Joaquín Ariño; Denis Alexander. Protein phosphatases. Springer. pp. 275–299. ISBN 978-3-540-20560-9

[B.G._Neel-27] “The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling”. Trends in Biochemical Sciences 28 (6): 284–293. (June 2003). doi:10.1016/S0968-0004(03)00091-4. ISSN 0968-0004. PMID 12826400.

[pmid10650943-28] “Potential involvement of FRS2 in insulin signaling”. Endocrinology 141 (2): 621–8. (Feb 2000). doi:10.1210/endo.141.2.7298. PMID 10650943.

[pmid11360177-29] “Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction”. Oncogene 20 (16): 1929–38. (Apr 2001). doi:10.1038/sj.onc.1204290. PMID 11360177.

[pmid9632781-30] “Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation”. Mol. Cell. Biol. 18 (7): 3966–73. (Jul 1998). doi:10.1128/MCB.18.7.3966. PMC 108981. PMID 9632781.

[pmid11940581-31] “Protein kinase C-alpha and protein kinase C-epsilon are required for Grb2-associated binder-1 tyrosine phosphorylation in response to platelet-derived growth factor”. J. Biol. Chem. 277 (26): 23216–22. (Jun 2002). doi:10.1074/jbc.M200605200. PMID 11940581.

[pmid9658397-32] “Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules”. Mol. Endocrinol. 12 (7): 914–23. (Jul 1998). doi:10.1210/mend.12.7.0141. PMID 9658397.

[pmid12135708-33] “Phosphatidylinositol 3-kinase regulates glycosylphosphatidylinositol hydrolysis through PLC-gamma(2) activation in erythropoietin-stimulated cells”. Cell. Signal. 14 (10): 869–78. (October 2002). doi:10.1016/S0898-6568(02)00036-0. PMID 12135708.

[pmid11782427-34] “PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2”. EMBO J. 21 (1–2): 72–82. (January 2002). doi:10.1093/emboj/21.1.72. PMC 125816. PMID 11782427.

[pmid10391903-35] “Gab2, a new pleckstrin homology domain-containing adapter protein, acts to uncouple signaling from ERK kinase to Elk-1”. J. Biol. Chem. 274 (28): 19649–54. (July 1999). doi:10.1074/jbc.274.28.19649. PMID 10391903.

[pmid11334882-36] “A yeast two-hybrid study of human p97/Gab2 interactions with its SH2 domain-containing binding partners”. FEBS Lett. 495 (3): 148–53. (April 2001). doi:10.1016/S0014-5793(01)02373-0. PMID 11334882.

[WolfJenkins2002-37] Wolf, I.; Jenkins, B. J.; Liu, Y.; Seiffert, M.; Custodio, J. M.; Young, P.; Rohrschneider, L. R. (2002). “Gab3, a New DOS/Gab Family Member, Facilitates Macrophage Differentiation”. Molecular and Cellular Biology 22 (1): 231–244. doi:10.1128/MCB.22.1.231-244.2002. ISSN 0270-7306. PMC 134230. PMID 11739737. "and associates transiently with the SH2 domain-containing proteins p85 and SHP2"

[pmid12403768-38] “SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130”. J. Biol. Chem. 278 (1): 661–71. (January 2003). doi:10.1074/jbc.M210552200. PMID 12403768.

[pmid10946280-39] “Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: structural receptor requirements for signal attenuation”. Journal of Immunology 165 (5): 2535–43. (Sep 2000). doi:10.4049/jimmunol.165.5.2535. PMID 10946280.

[pmid9388212-40] “Transmembrane domain of gp130 contributes to intracellular signal transduction in hepatic cells”. J. Biol. Chem. 272 (49): 30741–7. (Dec 1997). doi:10.1074/jbc.272.49.30741. PMID 9388212.

[pmid8995399-41] “Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases”. J. Biol. Chem. 272 (2): 1032–7. (January 1997). doi:10.1074/jbc.272.2.1032. PMID 8995399.

[pmid10747947-42] “Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk”. J. Biol. Chem. 275 (23): 17263–8. (Jun 2000). doi:10.1074/jbc.M000689200. PMID 10747947.

[pmid8041791-43] “Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras”. Proc. Natl. Acad. Sci. U.S.A. 91 (15): 7335–9. (Jul 1994). doi:10.1073/pnas.91.15.7335. PMC 44394. PMID 8041791.

[pmid9824671-44] “Direct binding of Shc, Grb2, SHP-2 and p40 to the murine granulocyte colony-stimulating factor receptor”. Biochim. Biophys. Acta 1448 (1): 70–6. (Nov 1998). doi:10.1016/S0167-4889(98)00120-7. PMID 9824671.

[pmid9362449-45] “Induced direct binding of the adapter protein Nck to the GTPase-activating protein-associated protein p62 by epidermal growth factor”. Oncogene 15 (15): 1823–32. (Oct 1997). doi:10.1038/sj.onc.1201351. PMID 9362449.

[pmid10212213-46] “Fyn kinase-directed activation of SH2 domain-containing protein-tyrosine phosphatase SHP-2 by Gi protein-coupled receptors in Madin-Darby canine kidney cells”. J. Biol. Chem. 274 (18): 12401–7. (Apr 1999). doi:10.1074/jbc.274.18.12401. PMID 10212213.

[pmid10080542-47] “Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells”. J. Leukoc. Biol. 65 (3): 372–80. (Mar 1999). doi:10.1002/jlb.65.3.372. PMID 10080542.

[pmid8702859-48] “Epidermal growth factor induces coupling of protein-tyrosine phosphatase 1D to GRB2 via the COOH-terminal SH3 domain of GRB2”. J. Biol. Chem. 271 (35): 20981–4. (Aug 1996). doi:10.1074/jbc.271.35.20981. PMID 8702859.

[pmid10976913-49] “Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B”. Mol. Endocrinol. 14 (9): 1338–50. (September 2000). doi:10.1210/me.14.9.1338. PMID 10976913.

[pmid9632636-50] “Grb10 identified as a potential regulator of growth hormone (GH) signaling by cloning of GH receptor target proteins”. J. Biol. Chem. 273 (26): 15906–12. (June 1998). doi:10.1074/jbc.273.26.15906. PMID 9632636.

[pmid19022774-51] “Constitutively active SHP2 cooperates with HoxA10 overexpression to induce acute myeloid leukemia.”. J Biol Chem 284 (4): 2549–67. (Jan 2009). doi:10.1074/jbc.M804704200. PMC 2629090. PMID 19022774.

[pmid8135823-52] “Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro”. Biochem. Biophys. Res. Commun. 199 (2): 780–5. (Mar 1994). doi:10.1006/bbrc.1994.1297. PMID 8135823.

[pmid7493946-53] “Adapter function of protein-tyrosine phosphatase 1D in insulin receptor/insulin receptor substrate-1 interaction”. J. Biol. Chem. 270 (49): 29189–93. (Dec 1995). doi:10.1074/jbc.270.49.29189. PMID 7493946.

[pmid10082579-54] “Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility”. Mol. Cell. Biol. 19 (4): 3125–35. (Apr 1999). doi:10.1128/mcb.19.4.3125. PMC 84106. PMID 10082579.

[pmid7642582-55] “Localization of the insulin-like growth factor I receptor binding sites for the SH2 domain proteins p85, Syp, and GTPase activating protein”. J. Biol. Chem. 270 (32): 19151–7. (Aug 1995). doi:10.1074/jbc.270.32.19151. PMID 7642582.

[pmid8505282-56] “The insulin receptor substrate 1 associates with the SH2-containing phosphotyrosine phosphatase Syp”. J. Biol. Chem. 268 (16): 11479–81. (Jun 1993). PMID 8505282.

[pmid9756938-57] “The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling”. J. Biol. Chem. 273 (41): 26908–14. (Oct 1998). doi:10.1074/jbc.273.41.26908. PMID 9756938.

[pmid8639815-58] “Tyrosine 425 within the activated erythropoietin receptor binds Syp, reduces the erythropoietin required for Syp tyrosine phosphorylation, and promotes mitogenesis”. Blood 87 (11): 4495–501. (June 1996). doi:10.1182/blood.V87.11.4495.bloodjournal87114495. PMID 8639815.

[pmid8912646-59] “SHPTP2 serves adapter protein linking between Janus kinase 2 and insulin receptor substrates”. Biochem. Biophys. Res. Commun. 228 (1): 122–7. (November 1996). doi:10.1006/bbrc.1996.1626. PMID 8912646.

[pmid10903717-60] “FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells”. Journal of Immunology 165 (3): 1197–209. (Aug 2000). doi:10.4049/jimmunol.165.3.1197. PMID 10903717.

[pmid9285412-61] “LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes”. Immunity 7 (2): 283–90. (Aug 1997). doi:10.1016/S1074-7613(00)80530-0. PMID 9285412.

[pmid18381291-62] “Structural and functional consequences of tyrosine phosphorylation in the LRP1 cytoplasmic domain”. J. Biol. Chem. 283 (23): 15656–64. (June 2008). doi:10.1074/jbc.M709514200. PMC 2414285. PMID 18381291.

[pmid11266449-63] “Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1”. J. Cell Biol. 152 (2): 325–34. (Jan 2001). doi:10.1083/jcb.152.2.325. PMC 2199605. PMID 11266449.

[pmid7691811-64] “Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor”. J. Biol. Chem. 268 (29): 21478–81. (Oct 1993). PMID 7691811.

[pmid10880513-65] “SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells”. J. Biol. Chem. 275 (36): 27845–50. (September 2000). doi:10.1074/jbc.M003428200. PMID 10880513.

[pmid11806999-66] “Molecular dissection of the signaling and costimulatory functions of CD150 (SLAM): CD150/SAP binding and CD150-mediated costimulation”. Blood 99 (3): 957–65. (Feb 2000). doi:10.1182/blood.V99.3.957. PMID 11806999.

[pmid11689425-67] “Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells”. EMBO J. 20 (21): 5840–52. (Nov 2001). doi:10.1093/emboj/20.21.5840. PMC 125701. PMID 11689425.

[pmid9344843-68] “Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells”. Biochem. Biophys. Res. Commun. 239 (2): 412–7. (Oct 1997). doi:10.1006/bbrc.1997.7480. PMID 9344843.

[pmid10617656-69] “Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation”. J. Biol. Chem. 275 (1): 599–604. (Jan 2000). doi:10.1074/jbc.275.1.599. PMID 10617656.

[pmid12060651-70] “Prolactin induces SHP-2 association with Stat5, nuclear translocation, and binding to the beta-casein gene promoter in mammary cells”. J. Biol. Chem. 277 (34): 31107–14. (Aug 2002). doi:10.1074/jbc.M200156200. PMID 12060651.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]