4exp

Structural highlights

Function

[IL34_MOUSE] Cytokine that promotes the proliferation, survival and differentiation of monocytes and macrophages. Promotes the release of proinflammatory chemokines, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, and in the regulation of bone resorption. Signaling via CSF1R and its downstream effectors stimulates phosphorylation of MAPK1/ERK2 AND MAPK3/ERK1 (By similarity). [CSF1R_MOUSE] Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]}

See Also

• Interleukin

References

1. ↑ van der Geer P, Hunter T. Tyrosine 706 and 807 phosphorylation site mutants in the murine colony-stimulating factor-1 receptor are unaffected in their ability to bind or phosphorylate phosphatidylinositol-3 kinase but show differential defects in their ability to induce early response gene transcription. Mol Cell Biol. 1991 Sep;11(9):4698-709. PMID:1652061
2. ↑ van der Geer P, Hunter T. Mutation of Tyr697, a GRB2-binding site, and Tyr721, a PI 3-kinase binding site, abrogates signal transduction by the murine CSF-1 receptor expressed in Rat-2 fibroblasts. EMBO J. 1993 Dec 15;12(13):5161-72. PMID:8262059
3. ↑ Myles GM, Brandt CS, Carlberg K, Rohrschneider LR. Tyrosine 569 in the c-Fms juxtamembrane domain is essential for kinase activity and macrophage colony-stimulating factor-dependent internalization. Mol Cell Biol. 1994 Jul;14(7):4843-54. PMID:8007983
4. ↑ Bourette RP, Myles GM, Choi JL, Rohrschneider LR. Sequential activation of phoshatidylinositol 3-kinase and phospholipase C-gamma2 by the M-CSF receptor is necessary for differentiation signaling. EMBO J. 1997 Oct 1;16(19):5880-93. PMID:9312046 doi:10.1093/emboj/16.19.5880
5. ↑ Lee AW, States DJ. Both src-dependent and -independent mechanisms mediate phosphatidylinositol 3-kinase regulation of colony-stimulating factor 1-activated mitogen-activated protein kinases in myeloid progenitors. Mol Cell Biol. 2000 Sep;20(18):6779-98. PMID:10958675
6. ↑ Dai XM, Ryan GR, Hapel AJ, Dominguez MG, Russell RG, Kapp S, Sylvestre V, Stanley ER. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood. 2002 Jan 1;99(1):111-20. PMID:11756160
7. ↑ Sakai H, Chen Y, Itokawa T, Yu KP, Zhu ML, Insogna K. Activated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts. Bone. 2006 Dec;39(6):1290-301. Epub 2006 Sep 1. PMID:16950670 doi:10.1016/j.bone.2006.06.012
8. ↑ Pakuts B, Debonneville C, Liontos LM, Loreto MP, McGlade CJ. The Src-like adaptor protein 2 regulates colony-stimulating factor-1 receptor signaling and down-regulation. J Biol Chem. 2007 Jun 22;282(25):17953-63. Epub 2007 Mar 11. PMID:17353186 doi:10.1074/jbc.M701182200
9. ↑ Takeshita S, Faccio R, Chappel J, Zheng L, Feng X, Weber JD, Teitelbaum SL, Ross FP. c-Fms tyrosine 559 is a major mediator of M-CSF-induced proliferation of primary macrophages. J Biol Chem. 2007 Jun 29;282(26):18980-90. Epub 2007 Apr 9. PMID:17420255 doi:10.1074/jbc.M610938200
10. ↑ Faccio R, Takeshita S, Colaianni G, Chappel J, Zallone A, Teitelbaum SL, Ross FP. M-CSF regulates the cytoskeleton via recruitment of a multimeric signaling complex to c-Fms Tyr-559/697/721. J Biol Chem. 2007 Jun 29;282(26):18991-9. Epub 2007 Apr 9. PMID:17420256 doi:10.1074/jbc.M610937200
11. ↑ Bourgin-Hierle C, Gobert-Gosse S, Therier J, Grasset MF, Mouchiroud G. Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-gamma2 and MAP kinases ERK1 and ERK2. Leukemia. 2008 Jan;22(1):161-9. Epub 2007 Nov 1. PMID:17972959 doi:10.1038/sj.leu.2404986
12. ↑ Hiraga T, Nakamura H. Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals. Int J Cancer. 2009 Jan 1;124(1):215-22. doi: 10.1002/ijc.23903. PMID:18814279 doi:10.1002/ijc.23903
13. ↑ Paniagua RT, Chang A, Mariano MM, Stein EA, Wang Q, Lindstrom TM, Sharpe O, Roscow C, Ho PP, Lee DM, Robinson WH. c-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis. Arthritis Res Ther. 2010;12(1):R32. doi: 10.1186/ar2940. Epub 2010 Feb 24. PMID:20181277 doi:10.1186/ar2940
14. ↑ Wei S, Nandi S, Chitu V, Yeung YG, Yu W, Huang M, Williams LT, Lin H, Stanley ER. Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol. 2010 Sep;88(3):495-505. doi: 10.1189/jlb.1209822. Epub 2010 May, 26. PMID:20504948 doi:10.1189/jlb.1209822
15. ↑ Lenzo JC, Turner AL, Cook AD, Vlahos R, Anderson GP, Reynolds EC, Hamilton JA. Control of macrophage lineage populations by CSF-1 receptor and GM-CSF in homeostasis and inflammation. Immunol Cell Biol. 2012 Apr;90(4):429-40. doi: 10.1038/icb.2011.58. Epub 2011 Jul, 5. PMID:21727904 doi:10.1038/icb.2011.58
16. ↑ Sampaio NG, Yu W, Cox D, Wyckoff J, Condeelis J, Stanley ER, Pixley FJ. Phosphorylation of CSF-1R Y721 mediates its association with PI3K to regulate macrophage motility and enhancement of tumor cell invasion. J Cell Sci. 2011 Jun 15;124(Pt 12):2021-31. doi: 10.1242/jcs.075309. Epub 2011, May 24. PMID:21610095 doi:10.1242/jcs.075309
17. ↑ Liu H, Leo C, Chen X, Wong BR, Williams LT, Lin H, He X. The mechanism of shared but distinct CSF-1R signaling by the non-homologous cytokines IL-34 and CSF-1. Biochim Biophys Acta. 2012 May 8. PMID:22579672 doi:10.1016/j.bbapap.2012.04.012