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Regulation of myeloproliferation and M2 macrophage programming by Lyn/Hck, SHIP and Stat5
Author(s) -
Xiao Wenbin,
Hong Hong,
Kawakami Yuko,
Lowell Clifford A.,
Kawakami Toshiaki
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.844.9
Subject(s) - lyn , autocrine signalling , microbiology and biotechnology , stat5 , paracrine signalling , syk , haematopoiesis , cancer research , macrophage , signal transduction , biology , chemistry , immunology , stem cell , proto oncogene tyrosine protein kinase src , tyrosine kinase , receptor , biochemistry , in vitro
Homeostasis of hematopoietic stem cells (HSCs) is finely regulated by extrinsic and intrinsic factors via various signaling pathways that control their proliferation, survival, and differentiation. Here we showed that loss of two Src family kinases, Lyn and Hck, or SH2‐containing inositol 5′‐phosphatase (SHIP) resulted in accelerated cell cycling, increased proliferation, reduced apoptosis, growth factor‐independent colony formation, and myeloid and M2 macrophage‐skewed differentiation of HSCs, eventually leading to unlimited myeloproliferation by activating Stat5 at least in part through secreted IL‐3 and GM‐CSF. The clinical features of these knockout mice are a myeloproferative disease and M2 macrophages‐associated lung inflammation, both originating from long‐term HSCs. Expression of a membrane‐bound form of SHIP in Lyn/Hck deficient HSCs restored the homeostasis of HSCs and prevented myeloproliferation and lung inflammation. Thus this study has defined a myeloproliferative transformation‐sensitive signaling pathway, composed of Lyn/Hck, SHIP, autocrine/paracrine cytokines, and Stat5, that regulates the homeostasis of HSCs and M2 macrophage programming.