Role of c-Kit and erythropoietin receptor in erythropoiesis
Introduction
The appropriate regulation of erythropoiesis is essential for both embryonic development and adult red cell production. During murine development, erythropoiesis first occurs within the blood islands of the embryo. This stage is characterized by the production of nucleated red cells that express embryonic globins. The next stage of erythropoiesis is characterized by a profound expansion of erythroid progenitors in the fetal liver starting around day 10 of gestation. This stage is characterized by the expression of a definitive adult pattern of globin molecules. Finally, erythropoiesis takes place within the bone marrow microenvironment in adult subjects.
In the last decade, utilizing genetic and biochemical approaches, several key intracellular as well as extracellular factors have been identified that regulate erythropoiesis. Cytokines and transcription factors have been extensively characterized as key players in regulating this process. In particular, the role of erythropoietin is indispensable for normal adult definitive erythropoiesis [1], [2]. The signaling events initiated by the binding of erythropoietin (Epo) to the Epo-receptor (Epo-R) induce proliferation, survival, as well as, differentiation of erythroid progenitors [3]. Likewise, c-Kit and stem cell factor (SCF) signaling pathway also plays an essential role in erythroid cell development [4], [5]. The importance of c-Kit/SCF interactions in erythroid lineage development is most apparent from studies performed utilizing White spotting (W) and Steel (Sl) mutant mice [4], [5]. These mice demonstrate erythroid and other lineage-specific defects due to inherited mutations within the c-Kit and SCF genes, respectively. Although, it has become clear that c-Kit/SCF and Epo-R/Epo signaling events are necessary for erythropoiesis, the signaling mechanisms by which these two receptor/ligand pairs regulate cellular responses in erythroid cells remain poorly defined. This review will summarize recent advances made towards understanding the role of signaling pathways that regulate red cell production via c-Kit and Epo-R.
Section snippets
White spotting (W) and Steel (Sl) loci
The phenotypic abnormalities in mice with mutations affecting the Dominant White Spotting (W) and Steel (Sl) loci (reduction in pigment cells, sterility, and macrocytic anemia with mast cell deficiencies) demonstrate the critical nature of the proteins encoded by these loci in the normal development of hematopoietic stem and progenitor cells, melanocytes, and germ cells [4], [5], [6], [7]. The W locus encodes the receptor tyrosine kinase c-Kit [8], [9], [10], and the Sl locus encodes the
Signaling via c-Kit receptor tyrosine kinase
The profound effects of SCF on expansion and survival of erythroid progenitor cells has raised considerable interest in the identification of critical signal transduction pathways activated by c-Kit in these cells. To this end, the binding of SCF to c-Kit results in dimerization and autophosphorylation of the receptor on several distinct cytoplasmic tyrosine residues which become binding sites for a variety of Src homology 2 domain-containing enzymes and adaptor proteins such as phospholipase
Signaling via erythropoietin receptor
Erythropoiesis is controlled to a large extent by signals derived from erythropoietin and erythropoietin receptors in addition to c-Kit. Epo-R belongs to the class I cytokine receptor family, and initiates signaling by activating Janus kinase (JAK) 2, which binds to Epo receptor dimers at a conserved Box 1 motif [65], [66] (Fig. 2, Fig. 3). Activated JAK2 phosphorylates the Epo-R at multiple cytoplasmic tyrosine residues, which results in the recruitment of Src homology (SH)-2 domain-containing
Mechanism of cooperation between c-Kit and erythropoietin receptor
Although SCF has been shown to induce some growth and survival of erythroid progenitors, its response is profoundly amplified in combination with Epo. This type of synergy between c-Kit and Epo-R has been described in experiments attempting to enumerate BFU-E and CFU-E formation in vitro as well as in vivo upon co-administering SCF and Epo. However, the basis for this synergism is poorly understood. To this end, biochemical studies have provided evidence for physical association between c-Kit
Role of SCF and Epo in therapy
Anemia is a common symptom associated with most cancer patients, and appears in all patients with hematological malignancies [120]. Cancer related anemia occurs primarily due to blood loss, bone marrow tumor infiltration, hemolysis, and folic acid deficiency [120]. For more than a decade, recombinant human Epo(rhEpo) has been used as a therapeutic agent to treat anemia in adults with cancer. This type of treatment results in increased hemoglobin production, improves the quality of life,
Veerendra Munugalavadla is a Postdoctoral Fellow in Dr. Kapur's laboratory in the Department of Pediatrics at the Indiana University School of Medicine in Indianapolis, Indiana.
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2021, Biochimica et Biophysica Acta - Molecular Cell ResearchGATA Factor-Mediated Gene Regulation in Human Erythropoiesis
2020, iScienceCitation Excerpt :To prove that this interplay between regulatory elements and GATA factors' binding is crucial to control gene expression during erythroid development, we focused on the KIT gene. A precise regulation of KIT expression is required for erythroid progenitor survival and proliferation and to achieve terminal erythroid maturation (Munugalavadla and Kapur, 2005). Indeed, we found that, in HSPC, KIT mRNA levels were relatively low and ∼65% cells poorly expressed KIT on the cell surface (median fluorescence intensity [MFI] = 17) (Figures 4A and 4B).
Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program
2017, Cell ReportsCitation Excerpt :The −77−/− R1 cells lacked GATA-1 protein (Figure 5F). The GATA-2 target gene Kit (Jing et al., 2008; Munugalavadla et al., 2005) encodes the c-Kit receptor tyrosine kinase that controls HSPC and erythroid precursor proliferation, differentiation, survival, and regeneration (Chabot et al., 1988; Hewitt et al., 2015, 2017; Munugalavadla and Kapur, 2005; Wojchowski et al., 2010). c-Kit is activated by SCF (Huang et al., 1990), a critical determinant of hematopoiesis (Ding and Morrison, 2013).
Veerendra Munugalavadla is a Postdoctoral Fellow in Dr. Kapur's laboratory in the Department of Pediatrics at the Indiana University School of Medicine in Indianapolis, Indiana.
Reuben Kapur is an Assistant Professor in the Department of Pediatrics, Molecular Biology and Biochemistry at the Indiana University School of Medicine in Indianapolis, Indiana.