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SH 2B3 ( LNK ) mutations from myeloproliferative neoplasms patients have mild loss of function against wild type JAK 2 and JAK 2 V617F
Author(s) -
KorenMichowitz Maya,
Gery Sigal,
Tabayashi Takayuki,
Lin Dechen,
Alvarez Rocio,
Nagler Ar,
Koeffler H. Phillip
Publication year - 2013
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12327
Subject(s) - jak2 v617f , point mutation , mutation , mutant , haematopoiesis , signal transducing adaptor protein , wild type , function (biology) , chemistry , loss function , myeloproliferative disorders , biology , cancer research , microbiology and biotechnology , genetics , phenotype , receptor , immunology , gene , stem cell
Summary Somatic point mutations in the PH domain of SH 2B3 ( LNK ), an adaptor protein that is highly expressed in haematopoietic cells, were recently described in patients with myeloproliferative neoplasms. We studied the effect of these mutations on the JAK 2 signalling pathway in cells expressing either wild type JAK 2 or the JAK 2 V617F mutation. Compared to wild type SH 2B3, PH domain mutants have mild loss of function, with no evidence for a dominant‐negative effect. Mutants retain binding capacity for JAK 2, an established SH 2B3 target, as well as for the adaptor proteins 14‐3‐3 and CBL . Our data suggest that the loss of SH 2B3 inhibitory function conferred by the PH domain mutations is mild and may collaborate with JAK 2 V617F and CBL mutations in order to promote either the development or the progression of myeloproliferative neoplasms.