Structure of macrophage colony stimulating factor bound to FMS: Diverse signaling assemblies of class III receptor tyrosine kinases
- 25 November 2008
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (47), 18267-18272
- https://doi.org/10.1073/pnas.0807762105
Abstract
Macrophage colony stimulating factor (M-CSF), through binding to its receptor FMS, a class III receptor tyrosine kinase (RTK), regulates the development and function of mononuclear phagocytes, and plays important roles in innate immunity, cancer and inflammation. We report a 2.4 A crystal structure of M-CSF bound to the first 3 domains (D1-D3) of FMS. The ligand binding mode of FMS is surprisingly different from KIT, another class III RTK, in which the major ligand-binding domain of FMS, D2, uses the CD and EF loops, but not the beta-sheet on the opposite side of the Ig domain as in KIT, to bind ligand. Calorimetric data indicate that M-CSF cannot dimerize FMS without receptor-receptor interactions mediated by FMS domains D4 and D5. Consistently, the structure contains only 1 FMS-D1-D3 molecule bound to a M-CSF dimer, due to a weak, hydrophilic M-CSF:FMS interface, and probably a conformational change of the M-CSF dimer in which binding to the second site is rendered unfavorable by FMS binding at the first site. The partial, intermediate complex suggests that FMS may be activated in two steps, with the initial engagement step distinct from the subsequent dimerization/activation step. Hence, the formation of signaling class III RTK complexes can be diverse, engaging various modes of ligand recognition and various mechanistic steps for dimerizing and activating receptors.Keywords
This publication has 29 references indexed in Scilit:
- Structural basis for stem cell factor–KIT signaling and activation of class III receptor tyrosine kinasesThe EMBO Journal, 2007
- Colony-stimulating factor-1 in immunity and inflammationCurrent Opinion in Immunology, 2006
- A Paracrine Loop between Tumor Cells and Macrophages Is Required for Tumor Cell Migration in Mammary TumorsCancer Research, 2004
- Colony-Stimulating Factor-1 Blockade by Antisense Oligonucleotides and Small Interfering RNAs Suppresses Growth of Human Mammary Tumor Xenografts in MiceCancer Research, 2004
- Genetic regulation of osteoclast development and functionNature Reviews Genetics, 2003
- Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defectsBlood, 2002
- Adipocyte macrophage colony-stimulating factor is a mediator of adipose tissue growth.JCI Insight, 1998
- Structure-function studies on human macrophage colony-stimulating factor (M-CSF)Molecular Reproduction and Development, 1997
- Emerging families of cytokines and receptorsCurrent Biology, 1993
- The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF 1Cell, 1985