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4dkd

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4dkd, resolution 3.00Å ()
Ligands: ,
Gene: IL34, C16orf77 (Homo sapiens), CSF1R, FMS (Homo sapiens)
Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Crystal Structure of Human Interleukin-34 Bound to Human CSF-1R

Publication Abstract from PubMed

Lacking any discernible sequence similarity, interleukin-34 (IL-34) and colony stimulating factor 1 (CSF-1) signal through a common receptor CSF-1R on cells of mononuclear phagocyte lineage. Here, the crystal structure of dimeric IL-34 reveals a helical cytokine fold homologous to CSF-1, and we further show that the complex architecture of IL-34 bound to the N-terminal immunoglobulin domains of CSF-1R is similar to the CSF-1/CSF-1R assembly. However, unique conformational adaptations in the receptor domain geometry and intermolecular interface explain the cross-reactivity of CSF-1R for two such distantly related ligands. The docking adaptations of the IL-34 and CSF-1 quaternary complexes, when compared to the stem cell factor assembly, draw a common evolutionary theme for transmembrane signaling. In addition, the structure of IL-34 engaged by a Fab fragment reveals the mechanism of a neutralizing antibody that can help deconvolute IL-34 from CSF-1 biology, with implications for therapeutic intervention in diseases with myeloid pathogenic mechanisms.

Structural Basis for the Dual Recognition of Helical Cytokines IL-34 and CSF-1 by CSF-1R., Ma X, Lin WY, Chen Y, Stawicki S, Mukhyala K, Wu Y, Martin F, Bazan JF, Starovasnik MA, Structure. 2012 Apr 4;20(4):676-87. Epub 2012 Apr 3. PMID:22483114

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[CSF1R_HUMAN] Note=Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers.[1][2][3][4][5][6] Note=Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.[7][8][9][10][11][12] Defects in CSF1R are the cause of leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) [MIM:221820]. An autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes.[13][14][15][16][17][18][19]

Function

[IL34_HUMAN] 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.[20][21][22][23] [CSF1R_HUMAN] 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.[24][25][26][27][28][29][30][31][32][33][34][35][36][37]

About this Structure

4dkd is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Ma X, Lin WY, Chen Y, Stawicki S, Mukhyala K, Wu Y, Martin F, Bazan JF, Starovasnik MA. Structural Basis for the Dual Recognition of Helical Cytokines IL-34 and CSF-1 by CSF-1R. Structure. 2012 Apr 4;20(4):676-87. Epub 2012 Apr 3. PMID:22483114 doi:10.1016/j.str.2012.02.010
  1. Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
  2. Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
  3. Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
  4. 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
  5. Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
  6. Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
  7. Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
  8. Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
  9. Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
  10. 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
  11. Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
  12. Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
  13. Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
  14. Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
  15. Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
  16. 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
  17. Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
  18. Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
  19. Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, Lash J, Wider C, Wojtas A, DeJesus-Hernandez M, Adamson J, Kouri N, Sundal C, Shuster EA, Aasly J, MacKenzie J, Roeber S, Kretzschmar HA, Boeve BF, Knopman DS, Petersen RC, Cairns NJ, Ghetti B, Spina S, Garbern J, Tselis AC, Uitti R, Das P, Van Gerpen JA, Meschia JF, Levy S, Broderick DF, Graff-Radford N, Ross OA, Miller BB, Swerdlow RH, Dickson DW, Wszolek ZK. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet. 2011 Dec 25;44(2):200-5. doi: 10.1038/ng.1027. PMID:22197934 doi:10.1038/ng.1027
  20. Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E, Halenbeck R, Wu G, Zhou A, Behrens D, Hollenbaugh D, Linnemann T, Qin M, Wong J, Chu K, Doberstein SK, Williams LT. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science. 2008 May 9;320(5877):807-11. doi: 10.1126/science.1154370. PMID:18467591 doi:10.1126/science.1154370
  21. Chihara T, Suzu S, Hassan R, Chutiwitoonchai N, Hiyoshi M, Motoyoshi K, Kimura F, Okada S. IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation. Cell Death Differ. 2010 Dec;17(12):1917-27. doi: 10.1038/cdd.2010.60. Epub 2010, May 21. PMID:20489731 doi:10.1038/cdd.2010.60
  22. Eda H, Zhang J, Keith RH, Michener M, Beidler DR, Monahan JB. Macrophage-colony stimulating factor and interleukin-34 induce chemokines in human whole blood. Cytokine. 2010 Dec;52(3):215-20. doi: 10.1016/j.cyto.2010.08.005. Epub 2010 Sep, 9. PMID:20829061 doi:10.1016/j.cyto.2010.08.005
  23. 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
  24. Bourette RP, Mouchiroud G, Ouazana R, Morle F, Godet J, Blanchet JP. Expression of human colony-stimulating factor-1 (CSF-1) receptor in murine pluripotent hematopoietic NFS-60 cells induces long-term proliferation in response to CSF-1 without loss of erythroid differentiation potential. Blood. 1993 May 15;81(10):2511-20. PMID:7683918
  25. Baran CP, Tridandapani S, Helgason CD, Humphries RK, Krystal G, Marsh CB. The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity. J Biol Chem. 2003 Oct 3;278(40):38628-36. Epub 2003 Jul 25. PMID:12882960 doi:10.1074/jbc.M305021200
  26. Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
  27. Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
  28. Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
  29. Taylor JR, Brownlow N, Domin J, Dibb NJ. FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor imatinib and mutation of Asp-802 to Val confers resistance. Oncogene. 2006 Jan 5;25(1):147-51. PMID:16170366 doi:10.1038/sj.onc.1209007
  30. Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E, Halenbeck R, Wu G, Zhou A, Behrens D, Hollenbaugh D, Linnemann T, Qin M, Wong J, Chu K, Doberstein SK, Williams LT. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science. 2008 May 9;320(5877):807-11. doi: 10.1126/science.1154370. PMID:18467591 doi:10.1126/science.1154370
  31. 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
  32. Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
  33. Chihara T, Suzu S, Hassan R, Chutiwitoonchai N, Hiyoshi M, Motoyoshi K, Kimura F, Okada S. IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation. Cell Death Differ. 2010 Dec;17(12):1917-27. doi: 10.1038/cdd.2010.60. Epub 2010, May 21. PMID:20489731 doi:10.1038/cdd.2010.60
  34. Eda H, Zhang J, Keith RH, Michener M, Beidler DR, Monahan JB. Macrophage-colony stimulating factor and interleukin-34 induce chemokines in human whole blood. Cytokine. 2010 Dec;52(3):215-20. doi: 10.1016/j.cyto.2010.08.005. Epub 2010 Sep, 9. PMID:20829061 doi:10.1016/j.cyto.2010.08.005
  35. 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
  36. Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
  37. Huang H, Hutta DA, Rinker JM, Hu H, Parsons WH, Schubert C, Desjarlais RL, Crysler CS, Chaikin MA, Donatelli RR, Chen Y, Cheng D, Zhou Z, Yurkow E, Manthey CL, Player MR. Pyrido[2,3-d]pyrimidin-5-ones: A Novel Class of Antiinflammatory Macrophage Colony-Stimulating Factor-1 Receptor Inhibitors (dagger). J Med Chem. 2009 Feb 4. PMID:19193011 doi:10.1021/jm801406h

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