The Inositol 5′-Phosphatase SHIP-1 and the Src Kinase Lyn Negatively Regulate Macrophage Colony-stimulating Factor-induced Akt Activity

Baran, Christopher P.; Tridandapani, Susheela; Helgason, Cheryl D.; Humphries, R. Keith; Krystal, Gerald; Marsh, Clay B.

doi:10.1074/jbc.m305021200

Cited by 93 publications

(95 citation statements)

References 47 publications

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“…In both B cells as well as mast cells, loss of Lyn results in hyperactivation of AKT and the mitogen-activated protein kinase extracellular signal-regulated kinase. In macrophages, loss of Lyn results in hypersensitivity to GM-CSF and M-CSF [19,34]. Previous studies have also shown that deficiency of Lyn in aged mice results in extramedullary hematopoiesis, as well as macrophage tumors in some cases [19,38].…”

Section: Discussionmentioning

confidence: 99%

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Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Orschell

Borneo

Munugalavadla

et al. 2008

Experimental Hematology

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Objective-Src family kinases (SFK) have been implicated in regulating growth factor and integrin-induced proliferation, migration, and gene expression in multiple cell types. However, little is known about the role of these kinases in the growth, homing, and engraftment potential of hematopoietic stem and progenitor cells.Results-Here we show that loss of hematopoietic-specific SFKs Hck, Fgr, and Lyn results in increased number of Sca-1 + Lin − cells in the bone marrow, which respond differentially to cytokine-induced growth in vitro and manifest a significant defect in the long-term repopulating potential in vivo. Interestingly, a significant increase in expression of adhesion molecules, known to coincide with the homing potential of wild-type bone marrow cells is also observed on the surface of SFK −/− cells, although, this increase did not affect the homing potential of more primitive Lin − Sca-1 + SFK −/− cells. The stem cell-repopulating defect observed in mice transplanted with SFK −/− bone marrow cells is due to the loss of Lyn Src kinase, because deficiency of Lyn, but not Hck or Fgr, recapitulated the long-term stem cell defect observed in mice transplanted with SFK −/− bone marrow cells.Conclusions-Taken together, our results demonstrate an essential role for Lyn kinase in positively regulating the long-term and multilineage engraftment of stem cells, which is distinct from its role in mature B cells and myeloid cells. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptEngraftment and reconstitution of normal hematopoiesis following transplantation of hematopoietic stem/progenitor (HSC/P) cells is the product of several important parameters, including the ability of hematopoietic stem cells (HSC) to home to, anchor within, and survive in specialized bone marrow (BM) niches, followed by timely proliferation and selfrenewal of stem cells for life-long hematopoiesis. While investigators have sought to understand the mechanisms behind each individual step, engraftment remains largely undefined.Besides homing and anchoring of HSC/P cells following transplantation, signals emanating from cytokine receptors also play a prominent role in regulating HSC/P cell growth and survival. In general, both positive and negative signals induced in response to cytokine stimulation contribute to this process. Deregulated signaling downstream from cytokine receptors can alter the growth and differentiation of these cells and, in some cases, contribute to leukemogenesis. Examples of molecules that are activated in response to hematopoietic growth factors include, but are not limited to, nonreceptor tyrosine kinases, such as Src family kinases (SFKs). SFKs function in signal transduction from growth factor receptors for granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, IL-5, stem cell factor (SCF), erythropoietin, M-CSF, G-CSF, thrombopoietin, and Flt3 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Although diverse cytokine receptors activat...

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Section: Discussionmentioning

confidence: 99%

“…Previous studies using Lyn-deficient mice have shown Lyn to play an essential role in maintaining signaling thresholds in B cells [21,25,26], myeloid cells, including in mast cells [14,19,[34][35][36][37]. Loss of Lyn results in reduced activation of phosphatases, such as SHIP, which results in hypersensitivity to cytokines [19,24,25].…”

Section: Discussionmentioning

confidence: 99%

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Orschell

Borneo

Munugalavadla

et al. 2008

Experimental Hematology

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“…Previous studies find that M-CSF-induced Akt phosphorylation is augmented in LynϪ/Ϫ macrophages, prompting us to postulate that hyperresponsibility to the cytokine promotes their enhanced propensity to OC differentiation (22). Lyn binds the M-CSF receptor, c-Fms, (data not shown), but M-CSF-mediated Akt and ERK phosphorylation are normal in Lyn-deficient cells committed to the OC phenotype.…”

Section: Lyn Retards Rankl-stimulated Bone Resorption In Vivomentioning

confidence: 90%

“…In addition, Lyn Ϫ/Ϫ mast cells hyperproliferate in response to growth factors (20,21). Importantly, Lyn deficiency enhances granulocyte-macrophagecolony stimulating factor (GM-CSF) and M-CSF sensitivity of macrophages (15,22).…”

mentioning

confidence: 99%

The Src family kinase, Lyn, suppresses osteoclastogenesis in vitro and in vivo

Kim

Zhang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Cite this article as Cold Spring Harb Perspect Biol 2014;6:a021857 2000; Lee et al 2011;Yu et al 2012), which is counterbalanced by a CSF-1R pTyr559/Lyn/ SHIP-1 pathway (Baran et al 2003). PI3K-independent pathways of CSF-1R-mediated survival involve phospholipase C (PLC) (Xu et al 1993) and Fms-interacting protein (FIMP) (Mancini et al 2004).…”

Section: Csf-1 Receptor Signaling In Myeloid Cellsmentioning

confidence: 99%

CSF-1 Receptor Signaling in Myeloid Cells

Stanley

Chiţu

2014

Cold Spring Harbor Perspectives in Biology

634

521

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The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). It plays important roles in development and in innate immunity by regulating the development of most tissue macrophages and osteoclasts, of Langerhans cells of the skin, of Paneth cells of the small intestine, and of brain microglia. It also regulates the differentiation of neural progenitor cells and controls functions of oocytes and trophoblastic cells in the female reproductive tract. Owing to this broad tissue expression pattern, it plays a central role in neoplastic, inflammatory, and neurological diseases. In this review we summarize the evolution, structure, and regulation of expression of the CSF-1R gene. We discuss the structures of CSF-1, IL-34, and the CSF-1R and the mechanism of ligand binding to and activation of the receptor. We further describe the pathways regulating macrophage survival, proliferation, differentiation, and chemotaxis downstream from the CSF-1R.

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The Inositol 5′-Phosphatase SHIP-1 and the Src Kinase Lyn Negatively Regulate Macrophage Colony-stimulating Factor-induced Akt Activity

Cited by 93 publications

References 47 publications

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

The Src family kinase, Lyn, suppresses osteoclastogenesis in vitro and in vivo

CSF-1 Receptor Signaling in Myeloid Cells

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