|  |
| |
| PTPN11 genomic organization and SHP-2 domain structure: Figure 1 : (A) The PTPN11 gene and SHP-2 domain characterization. The coding exons are shown as numbered filled boxes. The functional domains of the protein, comprising two tandemly arranged SH2 domains at the N terminus (N-SH2 and C-SH2) followed by a protein tyrosine phosphatase (PTP) domain, are shown below. Numbers below the domain structure indicate the amino-acid boundaries of those domains. (B) Three-dimensional structure of SHP-2 in its catalytically inactive conformation, as determined by Hof et al. (1998). Residues involved in catalysis are shown (space fill). Figure 2 : Location of SHP-2 mutated residues in human disease. (A) Noonan syndrome and LEOPARD syndrome (germ-line origin; N=224); (B) Noonan syndrome with juvenile myelomonocytic leukemia (germ-line origin; N=11); (C) hematologic malignancies, including juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia (somatic origin; N=97). The pictures show the C trace of SHP-2 in its catalytically inactive conformation. Affected residues are indicated with their side chains as black sticks. |
| |
Description | SHP-2 is a member of a small subfamily of cytoplasmic Src homology 2 (SH2) domain-containing protein tyrosine phosphatases. Both the N-SH2 and C-SH2 domains selectively bind to short amino acid motifs containing a phosphotyrosyl residue and promote SHP-2 association with activated receptors and other signaling partners. Crystallographic data indicate that the N-SH2 domain also interacts with the PTP domain using a separate site. As these subdomains show negative cooperativity, the N-SH2 domain functions as an intramolecular switch controlling SHP-2 catalytic activation. Specifically, the N-SH2 domain interacts with the PTP domain basally, blocking the catalytic site. Binding of the N-SH2 phosphopeptide-binding site to the phosphotyrosyl ligand promotes a conformational change of the domain that weakens the auto-inhibiting intramolecular interaction, making the catalytic site available to substrate, thereby activating the phosphatase. |
Expression | Widely expressed in both embryonic and adult tissues. |
Localisation | Cytoplasmic. It binds to activated cell surface receptors, cell adhesion molecules and scaffolding adapters. |
Function | SHP-2 functions as an intracellular signal transducer. It positively modulates signal flow in most circumstances, but can also function as negative regulator depending upon its binding partner and interactions with downstream signaling networks. SHP-2 positively controls the activation of the RAS/MAPK cascade induced by several growth factors, and negatively regulates JAK/STAT signaling. In most cases, SHP-2's function in intracellular signaling appears to be immediately proximal to activated receptors and upstream to RAS. The mechanisms of SHP-2's action and its physiological substrates are still poorly defined. However, both membrane translocation and PTPase activity are required for SHP-2 function. SHP-2 is required during development. Embryos nullizygous for Shp-2 have defects in gastrulation and mesodermal patterning resulting in severe abnormalities in axial and paraxial mesodermal structures. Shp-2 function is also required for development of terminal and skeletal structures, semilunar valvulogenesis in the heart, and hematopoiesis. |
Homology | PTPN6 (protein tyrosine phosphatase, non-receptor type, 6) previously known as SHP1 or SHP-1 (Src homology 2 domain-containing protein tyrosine phosphatase, 1). |
Note | At least two distinct classes of PTPN11 mutations have been identified in humans. The first group, which has germ-line origin, causes Noonan syndrome and closely related developmental disorders. The second group, acquired as a somatic event, has been documented in a heterogeneous group of hematologic malignancies and pre-leukemic disorders, and rarely in certain solid tumors. The vast majority of mutations affect residues residing at or close to the interface between the N-SH2 and PTP domains. Increasing evidence supports that both germ-line and somatic mutations promote SHP-2 gain-of-function by destabilizing the catalytically inactive conformation of the protein, and prolong signal flux through the RAS/MAPK pathway in a ligand-dependent manner. A mouse model bearing the NS-causative D61G mutation in the Ptpn11 gene has been recently generated and characterized. The Ptpn11D61G/D61G genotype is embryonic lethal. At day E13.5, these embryos are grossly edematous and hemorrhagic, have diffuse liver necrosis and severe cardiac defects. Heterozygous embryos exhibit cardiac defects, proportionate growth failure and perturbed craniofacial development. Hematologic anomalies include a mild myeloproliferative disease. Ptpn11D61G/+ embryonic fibroblasts exhibit a three-fold increased Shp-2 activity and increased association of Shp-2 with Gab1 after stimulation with EGF. Cell culture and whole embryo studies reveal that increased RAS/MAPK signaling is variably present, appearing to be cell-context specific. |
Germinal | Selection: 124A>G (T42A), 179-181delGTG (delGly60), 181-183delGAT (delAsp61), 182A>G (D61G), 184T>G (Y62D), 188A>G (Y63C), 214G>T (A72S), 215C>G (A72G), 218C>T (T73I), 228G>T,C (E76D), 236A>G (N79R), 317A>C (D106A), 836A>G (Y279C), 922A>G (N308D), 1403C>T (T468M), 1510A>G (M504V). |
Somatic | Selection: 181G>T (D61Y), 182A>T (D61V), 205G>A (E69K), 211-213TTT>AAA (F71K), 214G>A (A72T), 215C>T (A72V), 226G>A (E76K), 226G>C (E76Q), 227A>T (E76V), 227A>G (E76G), 227A>C (E76A), 1471C>T (P491S), 1472C>T (P491L), 1504T>C (S502P), 1504T>G (S502A), 1520C>A (T507K), 1528C>A (Q510K). |
A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains. |
Ahmad S, Banville D, Zhao Z, Fischer EH, Shen SH |
Proceedings of the National Academy of Sciences of the United States of America. 1993 ; 90 (6) : 2197-2201. |
PMID 7681589 |
|
A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. |
Andersen JN, Jansen PG, Echwald SM, Mortensen OH, Fukada T, Del Vecchio R, Tonks NK, M&oring;ller NP |
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2004 ; 18 (1) : 8-30. |
PMID 14718383 |
|
Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. |
Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL, Yang W, Pao LI, Gilliland DG, Epstein JA, Neel BG |
Nature medicine. 2004 ; 10 (8) : 849-857. |
PMID 15273746 |
|
Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. |
Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, Maris JM, Richardson A, Bardelli A, Sugarbaker DJ, Richards WG, Du J, Girard L, Minna JD, Loh ML, Fisher DE, Velculescu VE, Vogelstein B, Meyerson M, Sellers WR, Neel BG |
Cancer research. 2004 ; 64 (24) : 8816-8820. |
PMID 15604238 |
|
Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. |
Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B |
American journal of human genetics. 2002 ; 71 (2) : 389-394. |
PMID 12058348 |
|
Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. |
Fragale A, Tartaglia M, Wu J, Gelb BD |
Human mutation. 2004 ; 23 (3) : 267-277. |
PMID 14974085 |
|
Crystal structure of the tyrosine phosphatase SHP-2. |
Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE |
Cell. 1998 ; 92 (4) : 441-450. |
PMID 9491886 |
|
PTPN11 mutations in LEOPARD syndrome. |
Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP |
Journal of medical genetics. 2002 ; 39 (8) : 571-574. |
PMID 12161596 |
|
PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. |
Loh ML, Reynolds MG, Vattikuti S, Gerbing RB, Alonzo TA, Carlson E, Cheng JW, Lee CM, Lange BJ, Children's Cancer Group, Meshinchi S |
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 ; 18 (11) : 1831-1834. |
PMID 15385933 |
|
Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. |
Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH, Cheng JW, Lee CM, Stokoe D, Bonifas JM, Curtiss NP, Gotlib J, Meshinchi S, Le Beau MM, Emanuel PD, Shannon KM |
Blood. 2004 ; 103 (6) : 2325-2331. |
PMID 14644997 |
|
The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. |
Neel BG, Gu H, Pao L |
Trends in biochemical sciences. 2003 ; 28 (6) : 284-293. |
PMID 12826400 |
|
Germ-line and somatic PTPN11 mutations in human disease. |
Tartaglia M, Gelb BD |
European journal of medical genetics. 2005 ; 48 (2) : 81-96. |
PMID 16053901 |
|
Genotype-phenotype correlations in Noonan syndrome. |
Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, Reis A, Rauch A |
The Journal of pediatrics. 2004 ; 144 (3) : 368-374. |
PMID 15001945 |
|