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KIT

Official Full Name
KIT proto-oncogene, receptor tyrosine kinase
Organism
Homo sapiens
GeneID
3815
Background
This gene encodes a receptor tyrosine kinase. This gene was initially identified as a homolog of the feline sarcoma viral oncogene v-kit and is often referred to as proto-oncogene c-Kit. The canonical form of this glycosylated transmembrane protein has an N-terminal extracellular region with five immunoglobulin-like domains, a transmembrane region, and an intracellular tyrosine kinase domain at the C-terminus. Upon activation by its cytokine ligand, stem cell factor (SCF), this protein phosphorylates multiple intracellular proteins that play a role in in the proliferation, differentiation, migration and apoptosis of many cell types and thereby plays an important role in hematopoiesis, stem cell maintenance, gametogenesis, melanogenesis, and in mast cell development, migration and function. This protein can be a membrane-bound or soluble protein. Mutations in this gene are associated with gastrointestinal stromal tumors, mast cell disease, acute myelogenous leukemia, and piebaldism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2020]
Synonyms
PBT; SCFR; C-Kit; CD117; MASTC;
Bio Chemical Class
Kinase
Protein Sequence
MRGARGAWDFLCVLLLLLRVQTGSSQPSVSPGEPSPPSIHPGKSDLIVRVGDEIRLLCTDPGFVKWTFEILDETNENKQNEWITEKAEATNTGKYTCTNKHGLSNSIYVFVRDPAKLFLVDRSLYGKEDNDTLVRCPLTDPEVTNYSLKGCQGKPLPKDLRFIPDPKAGIMIKSVKRAYHRLCLHCSVDQEGKSVLSEKFILKVRPAFKAVPVVSVSKASYLLREGEEFTVTCTIKDVSSSVYSTWKRENSQTKLQEKYNSWHHGDFNYERQATLTISSARVNDSGVFMCYANNTFGSANVTTTLEVVDKGFINIFPMINTTVFVNDGENVDLIVEYEAFPKPEHQQWIYMNRTFTDKWEDYPKSENESNIRYVSELHLTRLKGTEGGTYTFLVSNSDVNAAIAFNVYVNTKPEILTYDRLVNGMLQCVAAGFPEPTIDWYFCPGTEQRCSASVLPVDVQTLNSSGPPFGKLVVQSSIDSSAFKHNGTVECKAYNDVGKTSAYFNFAFKGNNKEQIHPHTLFTPLLIGFVIVAGMMCIIVMILTYKYLQKPMYEVQWKVVEEINGNNYVYIDPTQLPYDHKWEFPRNRLSFGKTLGAGAFGKVVEATAYGLIKSDAAMTVAVKMLKPSAHLTEREALMSELKVLSYLGNHMNIVNLLGACTIGGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHAEAALYKNLLHSKESSCSDSTNEYMDMKPGVSYVVPTKADKRRSVRIGSYIERDVTPAIMEDDELALDLEDLLSFSYQVAKGMAFLASKNCIHRDLAARNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWMAPESIFNCVYTFESDVWSYGIFLWELFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAPAEMYDIMKTCWDADPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPVVDHSVRINSVGSTASSSQPLLVHDDV
Open
Disease
Acute myeloid leukaemia, Alzheimer disease, Bone/articular cartilage neoplasm, Brain cancer, Colorectal cancer, Gastrointestinal stromal tumour, Inflammatory arthropathy, Liver cancer, Lung cancer, Malignant intestine neoplasm, Mastocytosis, Mature B-cell lymphoma, Multiple myeloma, Myelodysplastic syndrome, Myeloproliferative neoplasm, Phakomatoses/hamartoneoplastic syndrome, Postoperative inflammation, Renal cell carcinoma, Solid tumour/cancer, Thrombocytopenia, Transplanted organ/tissue
Approved Drug
8 +
Clinical Trial Drug
10 +
Discontinued Drug
1 +

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Detailed Information

Essential to many cellular processes, KIT, also known as proto-oncogene c-Kit, codes a receptor tyrosine kinase (RTK). The importance of this gene transcends its first discovery as a homolog of the feline sarcoma viral oncogene v-kit. On human chromosome 4q11-12 the KIT gene codes for a 145-kDa protein with 21 exons and 976 amino acids. With an N-terminal extracellular domain, transmembrane region, and intracellular domain, this type III receptor tyrosine kinase is Starting a signaling cascade necessary for hematopoiesis, stem cell maintenance, gametogenesis, melanocyte and mast cell development, stem cell factor (SCF) activates c-KIT.

Structural Characteristics of the KIT Protein

Five immunoglobulin-like domains in the extracellular region, a hydrophobic α-helical transmembrane segment, and an intracellular kinase domain at the C-terminus define the conventional form of the KIT protein. The receptor changes conformally when it binds to SCF, which causes dimerization and later autophosphorylation. Among the various intracellular signaling pathways activated by this autophosphorylation are JAK-STAT, PI3K/AKT, and Ras-Erk. Cell proliferation, survival, differentiation, and death control all depend on these pathways.

Signaling Pathways Activated by KIT

1. PI3K/AKT Pathway: The phosphatidylinositol 3-kinase (PI3K) pathway is critically involved in mediating the anti-apoptotic effects of SCF. Upon activation, PI3K phosphorylates phosphatidylinositol (PIP), leading to increased levels of PIP3, which recruits proteins with pleckstrin homology (PH) domains to the plasma membrane, thus activating AKT. This activation is vital for promoting cell survival in response to SCF.

2. JAK-STAT Pathway: The JAK-STAT signaling pathway consists of receptor-associated tyrosine kinase (JAK) and transcription factors known as STATs. When SCF binds to the KIT receptor, JAK is activated and phosphorylates downstream targets, including STAT proteins. Activated STATs then translocate to the nucleus, where they regulate the transcription of genes involved in cell proliferation and survival.

3. Ras-Erk Pathway: The Ras-Erk pathway is integral to cell growth and differentiation. In this pathway, active Ras proteins recruit and activate the Raf-MEK-ERK signaling cascade, resulting in the activation of MAP kinases. This process ultimately influences gene expression and cellular behavior, promoting proliferation and survival.

Figure 1 describes the role of c-Kit in normal cells, highlighting the key functions of the Ras/Erk, PI3K, and JAK/STAT pathways in cell proliferation and survival.Figure 1. Signal transducer and activator of transcription tyrosine kinase domain c-Kit in normal cells. (Abbaspour Babaei M, et al., 2016)

Role of KIT in Cancer

Many cancers, including gastrointestinal stromal tumors (GASTs), melanomas, and acute myelogenous leukemia (AML), may result from dysregulation of KIT signaling. Usually occurring independently of SCF, mutations in the KIT gene cause constitutive activation of the receptor. Studies have shown, for example, that gain-of-function mutations in the KIT gene—especially in exon 11—cause GASTs to arise. These changes allow the receptor to dimerize and activate without ligand interaction, hence promoting unchecked cell growth.

About one-third of individuals with CBF-AML had KIT mutations, mostly affecting exons encoding the kinase domain and extracellular receptor domains. Usually resulting in a receptor with constitutively active behavior, the alterations help hematopoietic cells to undergo a malignant change. Analogously, in piebaldism, a rare hereditary disorder marked by pigment abnormalities, mutations in the KIT gene interfere with melanocyte growth and migration.

For tumors connected to abnormal KIT signaling, the prospect of targeted treatment is strong. Over forty clinical studies now concentrate on treatments meant to reduce KIT activation. Drugs designed to offset the consequences of KIT overactivity include imatinib, sunitinib, and nilotinib. In treating patients with GISTs and other cancers marked by KIT mutations, these medicines have been effective. However the development of opposition to these treatments, often resulting from secondary mutations in KIT, emphasizes the difficulty of targeting this pathway.

KIT in Development and Hematopoiesis

KIT is essential in embryonic development and hematopoiesis control outside of its function in cancer. Survival and proliferation of different progenitor cell types depend on the SCF-KIT connection throughout development. Hemopoietic stem cells (HSCs) develop and their differentiation into adult blood cells depends on KIT signaling. Furthermore stressing the relevance of this route in immunological responses, SCF-KIT signaling controls migration, survival, and function in mast cells.

Stem cell populations' maintenance mostly depends on the SCF-KIT axis. SCF generated by stromal cells binds to KIT on HSCs in the bone marrow, therefore encouraging their survival and self-renewal. Maintaining a constant supply of blood cells across a person's life depends on this interaction. Hemostatic problems like anemia and leukemias may result from disturbances of this signaling.

References:

  1. Abbaspour Babaei M, Kamalidehghan B, Saleem M, et al. Receptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells. Drug Des Devel Ther. 2016 Aug 1;10:2443-59.
  2. Du CY, Shi YQ, Zhou Y, et al. The analysis of status and clinical implication of KIT and PDGFRA mutations in gastrointestinal stromal tumor (GIST). J Surg Oncol, 2008, 98(3): 175-178.
  3. Lasota J, Corless CL, Heinrich MC, et al. Clinicopathologic profi le of gastrointestinal stromal tumors (GISTs) with primary KIT exon 13 or exon 17 mutations: a multicenter study on 54 cases. Mod Pathol, 2008, 21(4): 476-484.
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