近日，国际著名血液学杂志《BLOOD》网络版刊登了令人振奋的最新研究进展：白血病元凶是酪氨酸蛋白磷酸酶非受体型11（protein tyrosine phosphatase, non-receptor type 11,PTPN11）基因编码中的蛋白质shp-2作怪。这一发现无疑将对白血病的防治有重大贡献，该成果备受国内外医学界的广泛关注。课题主要负责人，浙江大学医学院附属二院血液科徐荣臻博士说，尽管利用这一发现要生产出攻克白血病的药物还有较长的路要走，但它就像是曙光，向人们预示了光明就会到来。
白血病，俗称血癌，是一种常见的严重危害人类健康的造血系统恶性肿瘤。在青少年恶性肿瘤中，白血病的发病率位居第一。骨髓移植治疗因配对困难无法全面开展，而且适合移植的也是白血病患者中的一部分。解开白血病病因之迷，将开辟治疗捷径。
做为临床医生，徐荣臻博士重复目睹了病人的绝望和痛苦后，转向病理研究。他在三个国家自然科学基金项目的支持政下开始着手从基因分子水平进行研究。他带领的课题组分析了白血病患者白血病细胞样本，多种不同类型人白血病细胞系，以及相应正常人血细胞中的 PTPN11基因序列，研究其编码的酪氨酸蛋白磷酸酶Shp-2的表达状态和功能进行系统。
结果发现，PTPN11基因编码的活性蛋白酶Shp-2在白血病细胞中呈异常分布与过度表达状态。继续顺藤摸瓜，徐荣臻博士课题小组发现在正常血细胞中，蛋白酶Shp-2安分地分布在细胞浆内，而在白血病细胞中，它“犯案作乱”，大批活跃地入侵细胞膜内侧和细胞核内。“这一‘犯罪现场’提示我们，蛋白酶Shp-2可能还是一个新的抗白血病药物靶分子。”徐荣臻为他们这些重要的原创性发现而兴奋不异，多年来的艰辛与清贫都被忘在脑后。这一重大研究写成论文发表之后，创下了浙江大学医学院本土科研工作者SCI影响因子纪录。]
原始出处：
Rongzhen Xu, Yingzi Yu, Shu Zheng, Xiaoying Zhao, Qinghua Dong, Zhiwen He, Yun Liang, Qinghua Lu, Yongmin Fang, Xiaoxian Gan, Xiaohua Xu, Suzhan Zhang, Qi Dong, Xiaohong Zhang, and Gen-Sheng Feng. Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia,Blood 2005 106: 3142-3149
有关PTPN11基因功能研究的近年来文献汇集
1. data suggest a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with juvenile myelomonocytic leukemia, Noonan syndrome/myeloproliferative disease, and Noonan syndrome PubMed
2. Presence of PTPN11 mutations in patients with Noonan syndrome indicates a reduced growth response to long-term human growth hormone treatment. PubMed
3. SHP-2 mutations in Noonan syndrome cause mild GH resistance by postreceptor signaling defect, partially compensated for by elevated GH secretion. May contribute to short stature phenotype in children with SHP-2 mutations and poor response to rhGH. PubMed
4. an important role for a PECAM1-SHP2-Tie2 pathway in flow-mediated signal transduction. PubMed
5. Missense mutations and the role of SHP-2 in signal transduction, development and hematopoiesis, as well as on the consequences of SHP-2 gain-of-function. Review. PubMed
6. Results show that PTPN11 mutations are rarely found in two isolated forms of congenital heart disease. PubMed
7. Most common mutation was A922G in exon 8. In exon 4 a mutation encoded C-SH2 domain of PTPN11 gene in two patients. A 218C-->T mutation was found in exon 3 in a patient with Noonan syndrome and mild juvenile myelomonocytic leukaemia. PubMed
8. Pathogenesis of Noonan syndrome and leukemia is associated with enhanced phosphatase activity of mutant SHP-2 PubMed
9. Tyr-992 and Tyr-1173 are required for phosphorylation of the epidermal growth factor receptor by ionizing radiation and modulation by SHP2 PubMed
10. data support the hypothesis that PTPN11 mutations induce hematopoietic progenitor hypersensitivity to GM-CSF due to hyperactivation of the Ras signaling axis PubMed
11. 10 genes were down-regulated following treatment of the T-ALL cells with 0.15 and 1.5 microg/mL of metal ores at 72 h PubMed
12. Mutations are rare in adult myelodysplastic syndromes and chronic myelomonocytic leukemia. PubMed
13. SHP-2 has a role in regulating IL-1-induced Ca2+ flux and ERK activation via phosphorylation of PLCgamma1 PubMed
14. SHP2 binds CAT and acquires a hydrogen peroxide-resistant phosphatase activity via integrin-signaling. PubMed
15. PTPN11 missense mutations are associated with acute myeloid leukemia PubMed
16. A missense mutation (836A-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in the patient with LEOPARD syndrome, whereas no mutation in PTPN11 gene was detected in the father or in additional family members PubMed
17. In contrast to childood MDS and AML, mutations in PTPN11 make little or no contribution to the pathogenesis of adult MDS and AML. PubMed
18. inhibition of NK cell cytotoxicity by KIR2DL5 was blocked by dominant-negative SHP-2, but not dominant-negative SHP-1, whereas both dominant-negative phosphatases can block inhibition by KIR3DL1. PubMed
19. wider role of PTPN11 lesions in leukemogenesis, but also a lineage-related and differentiation stage-related contribution of these lesions to clonal expansion. PubMed
20. PTPN11 mutations account for approximately 40% of Noonan syndrome patients. Type of cardiovascular lesions and occurrence of hematological abnormalities are different in mutation-positive and mutation-negative patients. PubMed
21. results reveal that Gab1 protein recruits SHP2 protein tyrosine phosphatase to dephosphorylate paxillin PubMed
22. SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies PubMed
23. SHP-2/Gab1 association is critical for linking EGFR to NF-kappaB transcriptional activity via the PI3-kinase/Akt signaling axis in glioblastoma cells PubMed
24. SHP-2 has a role as a positive regulator of cytokine receptor signaling by regulating ubiquitination/degradation pathways PubMed
25. PTPN11 mutations do not cause Costello syndrome PubMed
26. Required for RetM918T-induced Akt activation. Downstream mediator of mutated receptors RetC634Y and RetM918T. Acts as limiting factor in Ret-associated endocrine tumors, in neoplastic syndromes multiple endocrine neoplasia types 2A and 2B. PubMed
27. During platelet activation, a functionally active complex between SHIP-2, filamin, actin, and GPIb-IX-V may orchestrate the localized hydrolysis of PtdIns(3,4,5)P3 and thereby regulate cortical and submembraneous actin. PubMed
28. SHP-2 may function as an adaptor molecule downstream of the the prolactin receptor and highlight a new recruitment mechanism of SHP-2 substrates. PubMed
29. SHP-2 catalytic activity plays a direct role in the inhibitory function of killer cell Ig-like receptors, and SHP-2 inhibits NK cell activation in concert with SHP-1. PubMed
30. SHP2 positively regulates IL-2 induced MAPK activation in malignant T cells. SHP2 may not be involved in the activation of Stat3 or Stat5 in cutaneous T-cell lymphoma cells. PubMed
31. We sequenced the entire coding region of the PTPN11 gene in ten well-characterised CFC patients and found no base changes. We also studied PTPN11 cDNA in our patients and demonstrated that there are no interstitial deletions either. PubMed
32. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. PubMed
33. The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa PubMed
34. These data suggest, that there are two, largely distinct modes of negative regulation of gp130 activity, despite the fact that both SOCS3 and SHP2 are recruited to the same site within gp130. PubMed
35. SHP-2 is a dual-specificity protein phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues and plays an important role in modulating STAT function in gene regulation PubMed
36. absence of mutation in cases of cardiofaciocutaneous syndrome PubMed
37. Mutations in PTPN11/SHP2 underlie a common form of Noonan syndrome and confirm that the disease exhibits both allelic and locus heterogeneity. PubMed
38. Results indicate that Gab1 and SHP-2 promote the undifferentiated epidermal cell state by facilitating Ras/MAPK signaling. PubMed
39. activation state of alphaVbeta3 integrin is an important regulator of the duration of insulin-like growth factor I receptor phosphorylation and this regulation is mediated through changes in the subcellular localization of SHP-2 PubMed
40. Some PTPN11 mutations (e.g., Y279C) are associated with both the Noonan syndrome phenotype and with skin pigmentation anomalies, such as multiple lentigines or cafe au lait spots (LEOPARD syndrome). PubMed
41. PTPN11 mutations are responsible for Noonan syndrome in a substantial fraction of patients and that relatively infrequent features of Noonan syndrome, such as sensory deafness and bleeding diathesis, can also result from mutations of PTPN11. PubMed
42. interacts with siglec-11 PubMed
43. Band 3 is an anchor protein for and a target for SHP-2 tyrosine phosphatase in human erythrocytes. PubMed
44. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. PubMed
45. Specific SHP-2 partitioning in raft domains triggers integrin-mediated signaling via Rho activation PubMed
46. SHP-2 modulates phosphorylation of PDGF receptors, thereby controls RasGTP recruitment and Ras/MAP kinase signaling in the heterodimeric configuration of the PDGF receptors PubMed
47. upon translocation, CagA perturbs cellular functions by deregulating SHP-2
全面接触PTPN11基因
What is the official name of the PTPN11 gene?
The official name of this gene is “protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1).”
PTPN11 is the gene's official symbol. The PTPN11 gene is also known by other names, listed below.
What is the normal function of the PTPN11 gene?
The PTPN11 gene carries the instructions for making a protein called protein tyrosine phosphatase, nonreceptor type 11. This protein is involved in the generation of signals within cells that affect how cells function and how often they divide. During embryonic development, this protein plays a critical role in the development of the heart, blood cells, and other tissues.
What conditions are related to the PTPN11 gene?
Noonan syndrome - caused by mutations in the PTPN11 gene
Most mutations in the PTPN11 gene that cause Noonan syndrome result in a change in the sequence of amino acids (the building blocks of proteins) in protein tyrosine phosphatase, nonreceptor type 11. These changes are believed to cause the protein to be continuously active, rather than switching on and off in response to other cellular proteins. The constant activation causes the improper regulation of systems that control cell functions such as growth and division. This misregulation can result in the characteristics of Noonan syndrome. Mutations in other genes also cause Noonan syndrome, but these genes have not been identified.
cancers - increased risk from variations of the PTPN11 gene
Gene mutations can be acquired during a person's lifetime and are present only in certain cells. This type of mutation is called a somatic mutation, and it is not inherited. Somatic mutations in the PTPN11 gene can increase the risk of developing a type of blood cancer called juvenile myelomonocytic leukemia. Certain changes in this gene cause the protein to be continuously active. Overactivity of this particular protein tyrosine phosphatase results in the loss of regulation in pathways that control the production of immature blood cells. As a result, certain white blood cells are overproduced, leading to this type of leukemia.
Some studies indicate that somatic mutations in PTPN11 are also associated with other blood disorders including chronic myelomonocytic leukemia, myelodysplastic syndrome, nonsyndromic acute myeloid leukemia, and acute lymphocytic leukemia.
other disorders - caused by mutations in the PTPN11 gene
Mutations in the PTPN11 gene can cause Noonan-like/multiple giant cell lesion syndrome. This syndrome has many of the same signs and symptoms of Noonan syndrome, but individuals with this disorder also have giant cell lesions (groups of unusually large cells that often have more than one nucleus) in bones and soft tissues.
Mutations in the PTPN11 gene can also cause LEOPARD syndrome, or multiple lentigines syndrome. The acronym LEOPARD stands for lentigines (brown skin spots like freckles), ECG abnormalities (measurement of abnormal electrical heart activity), ocular hypertelorism (widely spaced eyes), pulmonary stenosis (narrowing of the artery from the heart to the lungs), abnormalities of genitalia (reproductive organs), retardation of growth, and deafness. These characteristics vary, however, even among affected individuals in the same family.
Where is the PTPN11 gene located?
Cytogenetic Location: 12q24
Molecular Location on chromosome 12: base pairs 111,319,255 to 111,410,436
The PTPN11 gene is located on the long (q) arm of chromosome 12 at position 24.
More precisely, the PTPN11 gene is located from base pair 111,319,255 to base pair 111,410,436 on chromosome 12.
See How do geneticists indicate the location of a gene? in the Handbook.
Where can I find additional information about PTPN11?
You and your healthcare professional may find the following resources about PTPN11 helpful.
Gene Reviews - Clinical summary Gene Tests - DNA tests ordered by healthcare professionals
You may also be interested in these resources, which are designed for genetics professionals and researchers.
PubMed - Recent literature
OMIM - Genetic disorder catalog (4 links)
Research Resources - Tools for researchers (4 links)
What other names do people use for the PTPN11 gene or gene products?
BPTP3 CFC Noonan syndrome 1 NS1 protein-tyrosine phosphatase 2C PTP-1D PTP2C SHP2 SH-PTP2 SH-PTP3
See How are genetic conditions and genes named? in the Handbook.
Where can I find general information about genes?
The Handbook provides basic information about genetics in clear language.
What is DNA? What is a gene? How does a gene make a protein? How can gene mutations cause disorders?
These links provide additional genetics resources that may be useful.
Genetics education Human Genome Project Resources for Genetic Researchers
What glossary definitions help with understanding PTPN11?
acute ; acute lymphocytic leukemia ; acute myeloid leukemia ; amino acid ; cancer ; chronic ; chronic myelomonocytic leukemia ; domain ; embryonic ; gene ; genitalia ; giant cell ; homology ; hypertelorism ; juvenile ; juvenile myelomonocytic leukemia ; lesion ; leukemia ; mutation ; myelodysplastic syndrome ; nucleus ; phosphatase ; protein ; pulmonary ; receptor ; sign ; somatic mutation ; stenosis ; symptom ; syndrome ; tissues ; tyrosine ; white blood cells
