Elsevier

Gene

Volume 401, Issues 1–2, 15 October 2007, Pages 38-45
Gene

Role of c-kit/SCF in cause and treatment of gastrointestinal stromal tumors (GIST)

https://doi.org/10.1016/j.gene.2007.06.017Get rights and content

Abstract

c-Kit encodes for the receptor tyrosine kinase (RTK) and belongs to type III receptor family. This includes platelet derived growth factor (PDGF) α and β and macrophage colony stimulating factor (mCSF) apart from others. Their characteristic features are the presence of five immunologlobulin like domains in the extracellular region and 70–100 residues long kinase insert domain in the cytoplasmic region. The RTKs activate several signaling pathways within the cells leading to cell proliferation, differentiation, migration or metabolic changes. The Kit ligand-stem cell factor (SCF) induces a rapid and complete receptor dimerization resulting in activation by autophosphorylation of the catalytic tyrosine kinase and generation of signal transduction leading to regulation of cell growth. Various mutations in c-kit such as insertions and deletions (without affecting reading frame) and point mutations in the inhibitory juxtamembrane (JM) domain encoded by exon 11 have been reported in gastrointestinal stromal tumors (GISTs). Thus, c-kit signaling is believed to play a role in tumorigenesis. Efforts are being made to control and treat these tumors by blocking kit signaling using Imatinib with varying degrees of success. This review deals with the features of c-kit, its ligand and roles in gastrointestinal stromal tumors.

Introduction

The basic function of the protein kinases is to catalyze the transfer of the γ-phosphate of ATP to the OH residue of the protein. On the basis of the residue providing the OH group for phosphorylation they can either be serine/threonine kinases or tyrosine kinases. In multicellular organisms, a fundamental mechanism for communication between cells is the binding of polypeptide ligands to cell surface receptors possessing tyrosine kinase activity. These receptor tyrosine kinases (RTKs) play a crucial role in cell proliferation, differentiation, migration or metabolic changes through different signaling pathways.

Around the mid-eighties of the 20th century, the receptors for factors functioning via RTKs as epidermal growth factor (EGF) (Ullrich et al., 1984), insulin (Ebina et al., 1985), and platelet derived growth factor (PDGF) (Yarden et al., 1986) were found to represent a family of closely related proteins that transduces growth regulatory signals across the plasma membrane. The common topologies of the RTKs include an extracellular ligand-binding domain, a single transmembrane segment and a cytoplasmic kinase domain. The kinase family is the second largest enzyme family (1.7% of all human genes) after the protease family (1.9%). This is the fifth largest gene family in humans after the C2H2 zinc finger protein (3%), G-protein coupled receptors (2.8%), the major histocompatibility complex protein family genes (2.8%) and the protease family (Puente and López-Otín, 2004). In humans, there are 518 protein kinase genes (478 typical and 40 atypical) comprising 385 protein-serine/threonine kinases, 90 protein tyrosine kinases (58 receptor and 32 non-receptor), and 43 tyrosine-kinase like proteins (Manning et al., 2002).

Section snippets

c-Kit: receptor for protein tyrosine kinase

Besmer et al. (1986) described the Kit gene as viral oncogene v-Kit from a feline sarcoma virus (HZ 4-FeSV). Although v-Kit encodes a protein that lacks extracellular and membrane-spanning sequences its structural features suggest its origin from the cellular protooncogene c-kit by transduction and truncation (Yarden et al., 1987). The protooncogene c-kit codes for a type III RTKs which also includes receptor for macrophage colony stimulating factor (CSF-1) and PDGF α and β (Yarden, 1987, Qiu,

Stem cell factor (SCF)—the Kit ligand

The c-kit ligand is known by different names such as mast cell growth factor (Copeland, 1990, Anderson, 1990), kit ligand (Huang et al., 1990), steel factor (Witte, 1990) and stem cell factor (SCF) (Zsebo et al., 1990). SCF is a non-covalent homodimer composed of two slightly wedged protomers where each protomer exhibits an anti-parallel four helix bundle fold (characteristic cytokine topology). Dimerization is mediated by polar and non-polar interactions between the two protomers with a large

c-kit/SCF expression

The expression of c-kit has been found in a variety of tissues ranging from embryonic cells to germ cells to epithelial cells. It is expressed on the hematopoietic stem cells and on human lung mast cells (Okayama et al., 1994), peripheral blood eosinophils (Yuan et al., 1997) and circulating basophils (Columbo et al., 1992). During embryonic development the c-kit is expressed in primordial germ cells (PGCs) from embryonic day 7.5 (E7.5) to E13.5 (Manova and Bachvarora, 1991) and SCF is

Signaling by c-kit/SCF

Binding of SCF homodimers to c-kit induces the creation of docking sites for several Src-homology 2 (SH2)-containing signal transduction molecule after receptor dimerization and autophosphorylation. Autophosphorylation of the receptor is carried out at the following tyrosine residues in humans: 568, 570, 703, 721, 730, 823, 900 and 936 (Roskoski, 2005).

c-Kit and gastrointestinal stromal tumor (GIST)

Signaling by the c-kit plays an important role in erythropoesis, lymphopoesis, mast cell development and function, megakaryopoesis, gametogenesis and melanogenesis. Since it is involved closely with regulation of cell division, any alteration in its activity may play a very crucial role in human neoplasms. Kit expression has been reported in a variety of human solid tumors such as mast cell tumors, germ cell tumors, ovarian carcinomas, malignant melanomas, GISTs, small cell lung cancer (SCLC),

Treatment of GIST

Imatinib mesylate is a derivative of 2-phenyaminopyrimidine and was initially developed by Novartis Pharma (Basel, Switzerland) for specific inhibition of PDGFR and Bcr–Abl as a product of gene fusion by translocation of chromosomes in patients with chronic myelogenous leukemia (CML). It has been successfully used for the treatment of CML. Its inhibitory effect on wild type Kit was reported later (Buchdunger et al., 2000). Thereafter it was found to inhibit various types of mutated Kit found in

Conclusion

Several approaches for treatment of GIST have been used with varying degrees of success. The United States Food and Drug Administration approved the use of Imatinib mesylate for the treatment of malignant metastatic and/or unresectable GIST with a recommended dose of 400 or 600 mg daily. A combination of surgery and Imatinib treatment has brought a new era of dealing with GISTs and several other tumors. Simultaneous treatment with Imatinib and RAD001 (mTOR inhibitor) is being considered (Rossi

Acknowledgments

This work was supported by a DBT Grant No. BT/PR2752/AAQ/01/113/2001 and DST Grant No. SP/SO/DO3/99 to SA, and a core grant from the Department of Biotechnology, Government of India, to the National Institute of Immunology, New Delhi. We thank Shri Khem Singh Negi for the technical assistance.

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