Gain- and Loss-of-Function Lyn Mutant Mice Define a Critical Inhibitory Role for Lyn in the Myeloid Lineage

Harder, Kenneth W.; Parsons, Linda M.; Armes, Jane E.; Evans, Natalie; Kountouri, Nicole; Clark, Roslyn; Quilici, Cathy; Grail, Dianne; Hodgson, George; Dunn, Ashley R.; Hibbs, Margaret L.

doi:10.1016/s1074-7613(01)00208-4

Cited by 157 publications

(240 citation statements)

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“…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]. Our studies reveal a positive role for Lyn in regulating long-term engraftment of stem cells.…”

Section: Discussionsupporting

confidence: 74%

“…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%

“…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%

“…Loss of Lyn results in reduced activation of phosphatases, such as SHIP, which results in hypersensitivity to cytokines [19,24,25]. 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.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, deficiency of Lyn alone affects both positive and negative aspects of receptor signaling in myeloid and lymphoid cells [18]. Lyn −/− mice are hyperresponsive to myeloid growth factors and develop a myeloproliferative disorder due, in part, to loss of negative regulation through SHP-1 and SHIP phosphatases [19]. The importance of regulating Lyn activation is further demonstrated by additional pathological changes that occur in Lyndeficient mice, including lethal antibody-mediated autoimmune disease [20][21][22][23].…”

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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: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

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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CD19 hyperexpression augments Sle1‐induced humoral autoimmunity but not clinical nephritis

Shi¹,

Xie²,

Chang³

et al. 2007

Arthritis & Rheumatism

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Objective. B cell hyperactivity is a common denominator in murine and human systemic lupus erythematosus. Some susceptibility genes in lupus are associated with B cell hyperactivity, but others are clearly not. While the Sle1 lupus susceptibility locus of NZM2410/NZW origin leads to chromatin-focused autoimmunity, genetically engineered overexpression of CD19 leads to "generalized" B cell hyperactivity. We undertook this study to determine the degree to which generalized B cell hyperactivity can amplify lupus pathogenesis.Methods. To elucidate the impact of generalized B cell hyperactivity on Sle1-triggered autoimmunity, B6 mice bearing the human CD19 transgene were rendered congenic for the Sle1 z genetic locus and phenotyped for serologic, cellular, and pathologic evidence of lupus.Results. As expected, B6.Sle1.hCD19 Tg/Tg mice, homozygous at Sle1 and bearing the hCD19 transgene, exhibited high levels of IgM and IgG anti-DNA/ antiglomerular autoantibodies, skewed B cell subsets, and profoundly activated B and T cells. Despite exhibiting glomerular IgM, IgG, and complement deposits, these mice did not exhibit accelerated mortality or any clinical evidence of renal dysfunction.Conclusion. Generalized B cell hyperactivity may augment humoral autoimmunity, but this may not suffice to engender end-organ disease in lupus. These findings allude to the presence of an additional distal checkpoint that dissociates pathogenic autoantibody formation and renal immunoglobulin deposition from the progression to clinical nephritis in lupus."Generalized B cell hyperactivity" has been documented in several murine models of lupus (1,2). This phenomenon is evidenced by the activated surface phenotype of B cells, heightened spontaneous secretion of antibodies by cultured B cells, and the expanded population of B1 cells seen in most murine models of lupus (3-8). Transfer studies involving allotype-marked bone marrow (as well as pre-B cells) and tetraparental chimera experiments have also indicated that these phenotypes are genetically encoded in a B cell-intrinsic manner (9-13). Generalized B cell hyperactivity has also been documented in patients with lupus (14-16). The advent of microsatellite-based linkage analysis has shed light on the genetic basis of B cell hyperactivity in lupus. Linkage analysis in several murine models has uncovered multiple lupus susceptibility loci (for review, see refs. 17-20). In particular, a couple of loci on mouse chromosome 4 have been identified by several investigators to be linked to autoantibody production or other features of B cell hyperactivity (21-28). When 1 of these loci, Sle2 of NZM2410/NZW origin, was introgressed onto the normal C57BL/6 (B6) background, it precipitated several B cell phenotypes including polyclonal hypergammaglobulinemia and elevated B1 cell formation (29-31).In addition to the above lessons gleaned from mapping studies in lupus, additional molecular insights have also arisen from "engineered" mouse models that exhibit lupus-like disease. For example, aberrant express...

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Macrophage Migration Inhibitory Factor Down‐Regulates the RANKL–RANK Signaling Pathway by Activating Lyn Tyrosine Kinase in Mouse Models

Mun

Lee

2014

Arthritis & Rheumatology

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Objective Macrophage migration inhibitory factor (MIF) is an important modulator of innate and adaptive immunity as well as local inflammatory response. We previously reported that MIF down-regulated osteoclastogenesis through a mechanism that requires CD74. In the current study, we examined if MIF modulates osteoclastogenesis through Lyn phosphorylation and if the down regulation of RANKL-mediated signaling requires the association of CD74, CD44 and Lyn. Methods CD74 knockout, CD44 knockout and Lyn knockout mouse models were used to investigate if Lyn requires these receptor and coreceptor. Effects of MIF on osteoclastogenesis were assessed using western blot analysis, siRNA targeted downregulation of Lyn and LynKO mice and real time imaging of Lyn molecules to surface proteins. Results MIF treatment induced Lyn expression and MIF down-regulated the RANKL-induced AP-1 and Syk-PCLγ cascade during osteoclastogenesis through activated Lyn tyrosine kinase. We also found by immunoprecipitation studies that MIF receptor(s) associated with Lyn in response to MIF treatment. Studies using siRNA specific for Lyn and LynKO mice confirmed our finding. Conclusions Our findings indicate that the tyrosine kinase, Lyn, is activated when MIF binds to its receptor, CD74 and co-receptor, CD44 and, in turn, down regulates the RANKL-mediated signaling cascade by suppressing NFATc1 protein expression through downregulation of AP-1 and calcium signaling components.

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Gain- and Loss-of-Function Lyn Mutant Mice Define a Critical Inhibitory Role for Lyn in the Myeloid Lineage

Cited by 157 publications

References 53 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

CD19 hyperexpression augments Sle1‐induced humoral autoimmunity but not clinical nephritis

Macrophage Migration Inhibitory Factor Down‐Regulates the RANKL–RANK Signaling Pathway by Activating Lyn Tyrosine Kinase in Mouse Models

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