Liu H, Chen X, Focia PJ, He X.. Structural basis for stem cell factor-KIT signaling and activation of class III receptor tyrosine kinases. Embo J 26: 891-901

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
The EMBO Journal (Impact Factor: 10.43). 03/2007; 26(3):891-901. DOI: 10.1038/sj.emboj.7601545
Source: PubMed


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.
    Full-text · Article · Dec 2014 · Molecular Reproduction and Development
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    • "Both the membrane-associated and soluble (SCF1–165) forms are biologically active [14]. The core of the protein required for activity comprises residues 1–141 and is reported to bind and activate the receptor Kit [15]–[17]. The function of the C-terminal domain of SCF1–165 is not yet known. "
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    ABSTRACT: Human stem cell factor initiates a diverse array of cellular responses, including hematopoiesis, cell proliferation, differentiation, migration and survival. To explore the relationship between its structure and function, we produced recombinant soluble human stem cell factor1-165 (wild type) and human stem cell factor1-141 (C-terminal truncated) in a yeast expression system and compared their biological activities and thermal stabilities. The biological activity of the two proteins was measured as a function of TF-1 cell viability and effects on downstream signaling targets after incubation. We found that these proteins enhanced cell viability and downstream signaling to a similar extent, in a dose-dependent manner. The biological activity of recombinant human stem cell factor1-165 was significantly greater than that of recombinant human stem cell factor1-141 after heating the proteins (100 ng/mL) at 25-110°C for 10 minutes (P<0.05 for all temperatures). In addition, circular dichroism spectral analysis indicated that β-sheet structures were altered in recombinant human stem cell factor1-141 but not recombinant human stem cell factor1-165 after heating at 90°C for 15 or 30 min. Molecular modeling and limited proteolytic digestion were also used to compare the thermo stability between human stem cell factor1-165 and human stem cell factor1-141. Together, these data indicate that stem cell factor1-165 is more thermostable than stem cell factor1-141.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "As discussed above, although similar situation exists between Kitlga and Kita at site II, the lack of electrostatic interaction at this site seems to be compensated by hydrophobic interaction and hydrogen bonds. However, there is limited hydrogen bond formation and hydrophobic interaction between Kitlgb and Kitb at site I due to the limited number of amino acids at this site as compared to site II and III, which is the same as the situation in mammals [43], [44]. Therefore the binding affinity between Kitlgb and Kitb at site I is expected to be weak. "
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    ABSTRACT: Consisting of Kit ligand and receptor Kit, the Kit system is involved in regulating many ovarian functions such as follicle activation, granulosa cell proliferation, and oocyte growth and maturation. In mammals, Kit ligand is derived from the granulosa cells and Kit receptor is expressed in the oocyte and theca cells. In the zebrafish, the Kit system contains two ligands (Kitlga and Kitlgb) and two receptors (Kita and Kitb). Interestingly, Kitlga and Kitb are localized in the somatic follicle cells, but Kitlgb and Kita are expressed in the oocyte. Using recombinant zebrafish Kitlga and Kitlgb, we demonstrated that Kitlga preferentially activated Kita whereas Kitlgb specifically activated Kitb by Western analysis for receptor phosphorylation. In support of this, Kitlgb triggered a stronger and longer MAPK phosphorylation in follicle cells than Kitlga, whereas Kitlga but not Kitlgb activated MAPK in the denuded oocytes, in agreement with the distribution of Kita and Kitb in the follicle and their specificity for Kitlga and Kitlgb. Further analysis of the interaction between Kit ligands and receptors by homology modeling showed that Kitlga-Kita and Kitlgb-Kitb both have more stable electrostatic interaction than Kitlgb-Kita or Kitlga-Kitb. A functional study of Kit involvement in final oocyte maturation showed that Kitlga and Kitlgb both suppressed the spontaneous maturation significantly; in contrast, Kitlgb but not Kitlga significantly promoted 17α, 20β-dihydroxy-4-pregnen-3-one (DHP) -induced oocyte maturation. Our results provided strong evidence for a Kit-mediated bi-directional communication system in the zebrafish ovarian follicle, which could be part of the complex interplay between the oocyte and the follicle cells in the development of follicles.
    Full-text · Article · Feb 2013 · PLoS ONE
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