Abstract：
:The SH2-containing tyrosine phosphatase Shp2 (PTPN11) is required for growth factor and cytokine signaling. Germline Shp2 mutations cause Noonan Syndrome (NS), which is associated with increased risk of juvenile myelomonocytic leukemia (JMML). Somatic Shp2 mutations occur in sporadic JMML and other leukemias. We found that Shp2 mutants associated with sporadic leukemias transform murine bone marrow cells, whereas NS mutants are less potent in this assay. Transformation requires multiple domains within Shp2 and the Shp2 binding protein Gab2, and is associated with hyperactivation of the Erk, Akt, and Stat5 pathways. Mutant Shp2-transduced BM causes a fatal JMML-like disorder or, less commonly, lymphoproliferation. Shp2 mutants also cause myeloproliferation in Drosophila. Mek or Tor inhibitors potently inhibit transformation, suggesting new approaches to JMML therapy.
journal_name
Cancer Celljournal_title
Cancer cellauthors
Mohi MG,Williams IR,Dearolf CR,Chan G,Kutok JL,Cohen S,Morgan K,Boulton C,Shigematsu H,Keilhack H,Akashi K,Gilliland DG,Neel BGdoi
10.1016/j.ccr.2005.01.010keywords:
subject
Has Abstractpub_date
2005-02-01 00:00:00pages
179-91issue
2eissn
1535-6108issn
1878-3686pii
S1535-6108(05)00031-0journal_volume
7pub_type
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