Structural basis for stem cell factor-KIT signaling and activation of class III receptor tyrosine kinases.

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
The EMBO Journal (Impact Factor: 10.75). 03/2007; 26(3):891-901. DOI: 10.1038/sj.emboj.7601545
Source: PubMed

ABSTRACT Stem cell factor (SCF) binds to and activates the KIT receptor, a class III receptor tyrosine kinase (RTK), to stimulate diverse processes including melanogenesis, gametogenesis and hematopoeisis. Dysregulation of KIT activation is associated with many cancers. We report a 2.5 A crystal structure of the functional core of SCF bound to the extracellular ligand-binding domains of KIT. The structure reveals a 'wrapping' SCF-recognition mode by KIT, in which KIT adopts a bent conformation to facilitate each of its first three immunoglobulin (Ig)-like domains to interact with SCF. Three surface epitopes on SCF, an extended loop, the B and C helices, and the N-terminal segment, contact distinct KIT domains, with two of the epitopes undergoing large conformational changes upon receptor binding. The SCF/KIT complex reveals a unique RTK dimerization assembly, and a novel recognition mode between four-helix bundle cytokines and Ig-family receptors. It serves as a framework for understanding the activation mechanisms of class III RTKs.

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    • "c-KIT is a tyrosine kinase receptor belonging to the type III receptor tyrosine kinase family, which also includes the platelet-derived growth factor receptor (PDGFR) and the macrophage colony stimulating factor receptor (Liu et al., 2007). Its specific ligand, stem cell factor (SCF), Abbreviations: c-KIT/[tr-KIT], kit [or truncated] tyrosine kinase receptor; GNNK, Gly-Asn-Asn-Lys peptide sequence; JAK, Janus kinase; LH, luteinizing hormone; MAPK, mitogen-activated protein kinase; [m/s]SCF, [membranebound/soluble] stem cell factor; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositol 3-kinase; PLCg, phospholipase C gamma. "
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    ABSTRACT: Maintaining the delicate balance between cell survival and death is of the utmost importance for the proper development of germ cells and subsequent fertility. On the other hand, the fine regulation of tissue homeostasis by mechanisms that control cell fate is a factor that can prevent carcinogenesis. c-KIT is a type III receptor tyrosine kinase activated by its ligand, stem cell factor (SCF). c-KIT signaling plays a crucial role in cell fate decisions, specifically controlling cell proliferation, differentiation, survival, and apoptosis. Indeed, deregulating the SCF/c-KIT system by attenuation or overactivation of its signaling strength is linked to male infertility and cancer, and rebalancing its activity via c-KIT inhibitors has proven beneficial in treating human tumors that contain gain-of-function mutations or overexpress c-KIT. This review addresses the roles of SCF and c-KIT in the male reproductive tract, and discusses the potential application of c-KIT target therapies in disorders of the reproductive system. Mol. Reprod. Dev. 2014. © 2014 Wiley Periodicals, Inc.
    Molecular Reproduction and Development 12/2014; 81(12). DOI:10.1002/mrd.22430 · 2.68 Impact Factor
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    • "First, it reveals that the cytokine-binding epitope on hCSF-1R is defined by domains 2 and 3 (Figure 3B). With the exception of the Flt3 ligand-receptor interaction, this feature of receptor-ligand engagement has emerged as a consensus blueprint of RTKIII activation in all other structurally characterized RTKIII complexes thus far (binary mCSF-1R D1-D3 :mCSF-1 complex (Chen et al., 2008), KIT D1-D3 (5):SCF (Liu et al., 2007; Yuzawa et al., 2007) and PDGFR D1-D3 :PDGF-B (Shim et al.)). Second, it shows that receptor homotypic interactions can be attributed to a broad interaction interface between the tandem D4 domains of hCSF-1R, while the membraneproximal D5 domains diverge away to a separation of ~65 Å (Figure 3B). "
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    ABSTRACT: The hematopoietic colony stimulating factor-1 receptor (CSF-1R or FMS) is essential for the cellular repertoire of the mammalian immune system. Here, we report a structural and mechanistic consensus for the assembly of human and mouse CSF-1:CSF-1R complexes. The EM structure of the complete extracellular assembly of the human CSF-1:CSF-1R complex reveals how receptor dimerization by CSF-1 invokes a ternary complex featuring extensive homotypic receptor contacts and striking structural plasticity at the extremities of the complex. Studies by small-angle X-ray scattering of unliganded hCSF-1R point to large domain rearrangements upon CSF-1 binding, and provide structural evidence for the relevance of receptor predimerization at the cell surface. Comparative structural and binding studies aiming to dissect the assembly principles of human and mouse CSF-1R complexes, including a quantification of the CSF-1/CSF-1R species cross-reactivity, show that bivalent cytokine binding to receptor coupled to ensuing receptor-receptor interactions are common denominators in extracellular complex formation.
    Structure 12/2011; 19(12):1762-72. DOI:10.1016/j.str.2011.10.012 · 6.79 Impact Factor
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    • "Specifically, it seems that the Raf-MEK-ERK pathway primarily modulates proliferation and cytokine synthesis, the PI3K-Rac2-Pak-p38 pathway modulates F-actin rearrangement and cellular motility, and AKT Figure 1 c-Kit structure and mutations found in human malignancies and experimental mouse models. The structure of c-Kit receptor is characterized by an extracellular ligand-binding region containing five immunoglobulin-like repeats (encoded by exon 9 of the Kit gene), a transmembrane sequence, an autoinhibitory juxtamembrane domain (exon 11) and two intracellular TK domains: an ATPbinding pocket (exon 13 and 14) and a kinase activation loop (exon 17) (Liu et al., 2007). Mutations in c-Kit extracellular region are found in about 9% of GIST patients and are sensitive to imatinib. "
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    ABSTRACT: c-Kit tyrosine kinase receptor and its ligand stem cell factor have multiple functions during development, whereas in adulthood they are mostly needed for stem cell (SC) maintenance and mast cell (MC) biology. c-Kit plays an essential tumor-cell-intrinsic role in many types of cancer, either providing the tumorigenic force when aberrantly activated or conferring stem-like features characterizing the most aggressive variants. A tumor-cell-extrinsic role occurs through c-Kit-dependent accessory cells (such as MCs) that infiltrate tumors and deeply influence their progression. c-Kit-targeted therapy with tyrosine kinase inhibitors (TKIs) may ideally work against both tumor and stromal cells. Here, we summarize the tumor-intrinsic and -extrinsic roles of c-Kit in cancer and discuss TKIs with their on- and off-targets, with a special emphasis on MCs as paradigmatic c-Kit-dependent accomplices for tumor progression.
    Oncogene 11/2010; 30(7):757-69. DOI:10.1038/onc.2010.494 · 8.56 Impact Factor
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