The Src kinase Lyn is a negative regulator of mast cell proliferation

Hernandez-Hansen, Valerie; Mackay, Graham A.; Lowell, Clifford A.; Wilson, Bridget S.; Oliver, Janet M.

doi:10.1189/jlb.0503224

Cited by 40 publications

(52 citation statements)

References 21 publications

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“…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%

“…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 activate SFKs in response to ligand binding, most of the data thus far has been derived by studying cell-line models using dominant negative and activating approaches.…”

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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%

mentioning

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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“…In some circumstances, Lyn positively impacts B-cell receptor (BCR) and CD40 signaling (16,17), yet Lyn Ϫ/Ϫ B cells are overactive in response to BCR triggering (18,19). 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).…”

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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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“…B cells from Lyn -/-mice were found to be hyper-responsive to BCR engagement (Chan et al, 1997;Hibbs et al, 2002), and to IL-4 stimulation (Janas et al, 1999). Lyn -/-mast cells were also more responsive to proliferative signals delivered by IL-3 or Stem Cell Factor (Hernandez-Hansen et al, 2004). Importantly, Lyn -/-mast cells were more responsive to FcεRI-dependent activation signals (Nishizumi and Yamamoto, 1997;Kawakami et al, 2000).…”

Section: Lynmentioning

confidence: 99%

Negative Signaling in Fc Receptor Complexes

Daëron

Lesourne

2006

Advances in Immunology

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Cell activation results from the transient displacement of an active balance between positive and negative signaling. This displacement depends in part on the engagement of cell surface receptors by extracellular ligands. Among these are Receptors for the Fc portion of immunoglobulins (FcRs). FcRs are widely expressed by cells of hematopoietic orign. When binding antibodies, FcRs provide these cells with immunoreceptors capable of triggering numerous biological responses in response to specific antigen. FcR-dependent cell activation is regulated by negative signals which are generated together with positive signals within signalosomes that form upon FcR engagement. Many molecules involved in positive signaling, including the FcRβ subunit, the src kinase lyn, the cytosolic adapter Grb2, the transmembrane adapters LAT and NTAL, are indeed also involved in negative signaling. A major player in negative regulation of FcR signaling is the inositol 5-phosphatase SHIP1. Several layers of negative regulation operate sequentially as FcRs are engaged by extracellular ligands of increasing valency. A background protein tyrosine phosphatasedependent negative regulation maintains cells in a « resting » state. SHIP1-dependent negative regulation can be detected as soon as high-affinity FcRs are occupied by antibodies in the absence of antigen. It increases when activating FcRs are engaged by multivalent ligands and, further when FcR aggregation increases, accounting for the bell-shaped dose-response curve observed in excess of ligand. Finally, F-actin skeleton-associated high-molecular weight SHIP1, recruited to phopshorylated ITIMs, concentrates in signaling complexes when activating FcRs are coengaged with inhibitory FcRs by immune complexes. Based on these data, activating and inhibitory FcRs could be used for new therapeutic approaches of immune disorders.

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The Src kinase Lyn is a negative regulator of mast cell proliferation

Cited by 40 publications

References 21 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

Negative Signaling in Fc Receptor Complexes

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