Expression of a Y559F Mutant CSF-1 Receptor in M1 Myeloid Cells: A Role for Src Kinases in CSF-1 Receptor-Mediated Differentiation

Marks, Denese C.; Csar, Xavier F.; Wilson, Nicholas J.; Novak, Ulrike; Ward, Alister C.; Kanagasundarum, Varuni; Hoffmann, Brigitte; Hamilton, John A.

doi:10.1006/mcbr.1999.0123

Cited by 32 publications

(90 citation statements)

References 22 publications

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“…4B) confirm the central role of the Erk1/2 pathway in CSF-1-induced differentiation (Wilson et al 2005). In myeloblasts, a CSF-1R pTyr-559/SFK pathway initiates the activation of STAT3 (Marks et al 1999) and Erk1/ 2 and the inactivation of PP2A, which plays a significant role in enhancing Erk1/2-mediated macrophage differentiation . In multipotent cells, via a SFK-independent pathway, Gab2 becomes tyrosine phosphorylated, associating with signaling molecules, including Grb2, Shp2, and p85, to activate Erk1/2 and differentiation (Liu et al 2001).…”

Section: Csf-1 Receptor Signaling In Myeloid Cellsmentioning

confidence: 53%

CSF-1 Receptor Signaling in Myeloid Cells

Stanley

Chiţu

2014

Cold Spring Harbor Perspectives in Biology

555

450

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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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Section: Csf-1 Receptor Signaling In Myeloid Cellsmentioning

confidence: 53%

CSF-1 Receptor Signaling in Myeloid Cells

Stanley

Chiţu

2014

Cold Spring Harbor Perspectives in Biology

555

450

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“…Therefore, blocking SFK activity with PP2 or SU6656 totally abrogated M-CSF differentiation signal in FD-Fms cells, which represents a more dramatic response than that previously reported in M1-Fms cells. 22 These unequivocal data also support the idea that SFK inhibitors would specifically target the signaling pathways responsible for M-CSFinduced differentiation.…”

Section: Effects Of the Sfk Inhibitor Pp2 On Sfk And M-csfr Kinase Acmentioning

confidence: 53%

“…Studies with M1 and 32D murine myeloid cell lines demonstrated Src-family kinases (SFK) binding to activated M-CSFR 21 and partial impairment of M-CSF-induced differentiation by the src kinase inhibitor PP2. 22 In addition to activation of specific signaling pathways, another important aspect of M-CSF signaling specificity is the strength and duration of signaling. It has long been known that continuous M-CSF stimulation is required for progression throughout the G1 phase of cell cycle and induction of early response genes.…”

Section: Introductionmentioning

confidence: 99%

Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-γ2 and MAP kinases ERK1 and ERK2

et al. 2007

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Macrophage colony-stimulating factor (M-CSF) has been found to be involved in multiple developmental processes, especially production of cells belonging to the mononuclear phagocyte system. The decision of myeloid progenitor cells to commit to differentiation depends on activation levels of the mitogenactivated protein kinases (MAPK), ERK1 and ERK2. Using the murine myeloid progenitor cell line FD-Fms, we show here that persistent activity of Src-family kinases (SFK) is necessary for FD-Fms cell differentiation to macrophages in response to M-CSF. Chemical inhibition of SFK blocked FD-Fms cell differentiation while it caused strong inhibition of the late phosphorylation of phospholipase C (PLC)-c2 and MAPK. The PLC inhibitor U73122, previously shown to block M-CSF-induced differentiation, strongly decreased long-term MAPK phosphorylation. Interestingly, inhibiting SFK with SU6656 or the MAPK kinases MEK with U0126 significantly impaired development of mononuclear phagocytes in cultures of mouse bone marrow cells stimulated with M-CSF. Collectively, results support a model in which SFK are required for sustained PLC activity and MAPK activation above threshold required for commitment of myeloid progenitors to macrophage differentiation.

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“…26 Meanwhile, it is known that the tyrosine located in the juxtamembrane domain of Fms (Y561 in human and Y559 in murine) serves as a binding site for Src kinases including Hck when the residue is autophosphorylated. [51][52][53][54] However, when coexpressed with Hck, Nef also down-regulated a Fms mutant in which the tyrosine residue was replaced with phenylalanine (data not shown). Thus, the active Hck at the Golgi may interact with Fms via unidentified site(s) or form complexes with Fms indirectly.…”

Section: Discussionmentioning

confidence: 91%

“…Our finding that the degree to which the active Hck accumulated at the Golgi correlated well with that of the down-regulation of Fms ( Figures 4B,5B) strongly suggested that Nef down-regulated Fms through both the activation of Hck and the accumulation of the active Hck at the Golgi. The idea may answer why Hck, the downstream effector molecule important for the Fms signaling pathways, 38,[50][51][52][53] is involved in the downregulation of Fms by Nef.…”

Section: Discussionmentioning

confidence: 99%

Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor

Hiyoshi¹,

Suzu²,

Yoshidomi³

et al. 2008

Blood

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Nef is a multifunctional pathogenetic protein of HIV-1, the interaction of which with Hck, a Src tyrosine kinase highly expressed in macrophages, has been shown to be responsible for the development of AIDS. However, how the Nef-Hck interaction leads to the functional aberration of macrophages is poorly understood. We recently showed that Nef markedly inhibited the activity of macrophage colonystimulating factor (M-CSF), a primary cytokine for macrophages. Here IntroductionHIV-1 infections lead to the development of AIDS by causing progressive degeneration of the immune system. [1][2][3] The main cellular targets of HIV-1 are CD4 ϩ T cells and macrophages, and the depletion of CD4 ϩ T cells caused by an infection is suggested to account for many aspects of the pathogenesis of HIV-1. [1][2][3] Meanwhile, a number of studies have revealed the functional aberration of HIV-1-infected macrophages. 4,5 Infected macrophages showed an altered profile of the production of cytokine/chemokines 4 or migratory capacity, 5 which might contribute to the uncontrolled homeostasis of the immune system. Indeed, functional analyses of HIV-1 Nef protein have revealed that macrophages as well as CD4 ϩ T cells play an important role in the development of AIDS.Nef is a 25-to 30-kDa protein with no enzymatic activity encoded by the HIV-1 genome. 6,7 Studies of HIV-1-infected patients have clearly demonstrated Nef to be a critical determinant of the development of AIDS: HIV-1 strains without an intact Nef gene were frequently isolated from nonprogressive long-term survivors. 8,9 Subsequent study of HIV-1 transgenic mice confirmed the pathogenetic activity of Nef: targeted expression of the entire coding sequence of HIV-1 in CD4 ϩ T cells and macrophages caused a severe AIDS-like disease in mice, which was completely abolished by the disruption of the Nef gene. 10 Importantly, only an amino acid substitution in the proline-rich (PxxP) motifs of Nef was sufficient to protect mice from the development of AIDS-like disease. 11 A number of studies have revealed that Nef interacts with a subset of cellular Src family tyrosine kinases, via the PxxP motifs. 12-15 The Nef PxxP motifs had an affinity for the Src homology (SH3) domain of Hck, Lyn, and possibly c-Src, but not of Fgr, Fyn, Lck, In particular, the interaction between the Nef PxxP motifs and the Hck SH3 domain was likely to be important, because the interaction caused the activation of Hck. [13][14][15] Indeed, a study with HIV-1 transgenic mice clearly demonstrated the importance of the Nef-Hck interaction for the development of AIDS: the appearance of the AIDS-like disease was significantly delayed when the HIV-1 transgenic mice expressing an intact Nef gene were crossed with an hck Ϫ/Ϫ background. 11 Given that Hck is expressed in macrophages but not in CD4 ϩ T cells, 16 the finding indicates that the Nef-Hck interaction in macrophages is at least in part responsible for the development of AIDS. However, little is known of the molecular mechanisms by which the Nef-Hck interaction c...

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Expression of a Y559F Mutant CSF-1 Receptor in M1 Myeloid Cells: A Role for Src Kinases in CSF-1 Receptor-Mediated Differentiation

Cited by 32 publications

References 22 publications

CSF-1 Receptor Signaling in Myeloid Cells

CSF-1 Receptor Signaling in Myeloid Cells

Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-γ2 and MAP kinases ERK1 and ERK2

Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor

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