Normal and Oncogenic Forms of the Receptor Tyrosine Kinase Kit

Abstract

Kit is a receptor tyrosine kinase (RTK) that binds stem cell factor. This receptor ligand combination is important for normal hematopoiesis, as well as pigmentation, gut function, and reproduction. Structurally, Kit has both an extracellular and intracellular region. The intracellular region is comprised of a juxtamembrane domain (JMD), a kinase domain, a kinase insert, and a carboxyl tail. Inappropriate expression or activation of Kit is associated with a variety of diseases in humans. Activating mutations in Kit have been identified primarily in the JMD and the second part of the kinase domain and have been associated with gastrointestinal stromal cell tumors and mastocytosis, respectively. There are also reports of activating mutations in some forms of germ cell tumors and core binding factor leukemias. Since the cloning of the Kit ligand in the early 1990s, there has been an explo sion of information relating to the mechanism of action of normal forms of Kit as well as activated mutants. This is important because understanding this RTK at the biochemical level could assist in the development of therapeutics to treat primary and secondary defects in the tissues that require Kit. Furthermore, understanding the mechanisms mediating transformation of cells by activated Kit mutants will help in the design of interventions for human disease associated with these mutations. The objective of this review is to summarize what is known about normal and oncogenic forms of Kit. We will place particular emphasis on recent developments in understanding the mechanisms of action of normal and activated forms of this RTK and its association with human disease, particularly in hematopoietic cells.

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

“…Ligand-independent activation of c-KIT can be caused by different types of mutations that have been reported in AML and also in other human malignancies (including mast cell disorders, gastrointestinal stromal tumors, and testicular germ cell tumors). 50 Gain-of-function mutations may affect either the extracellular portion of c-KIT receptor, believed to play a role in the dimerization (in-frame insertion/deletions of exon 8 that all result in loss of the acid aspartic residue at amino acid 419), or the JMD (ITD of exon 11), or the structure of the AL in the TKD, such as the substitution of a single amino acid in exon 17 (mostly mutation D816V, and less commonly other mutations affecting codon 816 (D816Y/H/F/I), 821, 822 or 823). [51][52][53][54] Codon 816 c-KIT mutations were shown to induce constitutive activation of PI3K and downstream of PI3K, Jnk1 and Jnk2, as well as STAT3 and upregulation of STAT3 downstream targets, such as BLCXL and MYC.…”

Receptor tyrosine kinase transmembrane domains

“…[45][46][47][48][49][50] The importance of the JM domain in signaling is evident from several mutations, deletions and insertions in this domain that can lead to cancer. [51][52][53] In addition, recent studies have provided evidence for the active role of the JM domains in regulating RTK activity.…”

c-Kit mutants require hypoxia-inducible factor 1α to transform melanocytes

“…These phosphorylation events create docking sites for specific Src homology 2 (SH2) domain-containing proteins, which in turn control various intracellular signaling pathways. Numerous signaling molecules have been identified as binding partners for specific phospho-tyrosine (pTyr) residues on activated c-Kit, including the p85 subunit of the phosphatidyl-inositol-3 kinase (PI3K), phospholipase C, the Grb2 and Grb7 adapter proteins, Src family kinases and the protein tyrosine phosphatases SHP-1 and SHP-2 (Lennartsson et al, 2005). The recruitment of binding partners is cell specific and will determine the effect of SCF on each cell type.…”