KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog)
2015-11-01 Lars Rönnstrand , Johan Lennartsson AffiliationIdentity
HGNC
LOCATION
4q12
IMAGE
LEGEND
KIT (4q12) - Courtesy Mariano Rocchi
LOCUSID
ALIAS
C-Kit,CD117,MASTC,PBT,SCFR
FUSION GENES
DNA/RNA
Description
The KIT gene located on human chromsome 4q11 and contains 21 exons. Exon1 encodes the initation codon, exon 2-9 encodes the extracellular domain, exon 10 the transmembrane region and exons 11-21 the intracellular part.
Transcription
The 5.23 kb mRNA is alternatively spliced into two isoforms differing in the presence or absence of exon 9. This splicing gives rise to KIT variants that differ by the presence or absence of the amino acid sequence GNNK (denoted KIT and KITA, respectively). In addition there is alterative splicing occurring in humans, but not in mice, giving rise of isoforms that differ by the presence or absence of a serine residue in the kinase insert region. In postmeiotic germ cells a shorter KIT transcript is expressed that gives rise to a truncated version of KIT (tr-KIT) containing part of the kinase domain and the C-terminal tail.
Proteins
Description
976 aa; 145 kDa; type III receptor tyrosine kinase; glycoprotein; contains an extracellular domains with 5 Ig-like loops, a highly hydrophobic transmembrane domain (23 aa), and an intracellular domain with tyrosine kinase activity split by a kinase insert (KI) in an ATP-binding region and in the phosphotransferase domain. Tr-KIT does not contain the whole kinase domain and is therefore kinase inactive.
Expression
Hematopoietic stem cells, mast cells, melanocytes, germ-cell lineages and ICCs (Interstitial cells of Cajal). Expression pattern in the mouse suggest that KIT may play a role in tissues such as nervous system, placenta, heart, lung and midgestational kidneys.
Localisation
Plasma membrane. The truncated tr-KIT lacks the transmembrane domain and is hence not present at the plasma membrane.
Function
KIT is a cell surface receptor with tyrosine kinase activity; binding of ligand KITLG (also denoted MGF or SCF) induces receptor dimerization, autophosphorylation and signal transduction via molecules containing SH2- domains. KIT signaling leads to cell proliferation, survival, migration and differentiation.
Loss-of-function mutations.
Gain-of-function mutations.
Mutations
Note
See figures Loss-of-function mutations and Gain-of-function mutations.
Implicated in
Entity name
Disease
Autosomal dominant disorder of pigmentation; loss of function abnormalities of the KIT gene have been demonstrated in 59% of the typical patients.
Entity name
Familial Gastrointestinal Stromal Tumors and sporadic gastrointestinal stromal tumors (GISTs)
Disease
GISTs are the most common mesenchymal tumors in the human digestive tract; they originate from KIT-expressing cells (ICCs). All GISTs express KIT which is frequently (80-85% of the cases) mutated in exon 11 encoding the juxtamembrane domain. However, also mutations in exon 9 (encoding the extracellular region) and 17 (encoding a region around the activation loop in the kinase domain) have been found. Most GIST cells produce SCF thus establishing autocrine stimulation.
Entity name
Disease
Mast cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, gastrointestinal tract and skin; gain of function mutations are detected in most patients. About 90% of patients with systemic mastocytosis have mutation in exon 17 in KIT, often Asp-816 is replaced with Val. In children with systemic mastocytosis the frequency of KIT mutations in exon 17 is lower (about 40%), but mutations in other KIT regions are found in 40% of the children, for example mutation in exon 8 and 9 (encoding Ig-like domain 5 in the extracellular region of KIT).
Prognosis
The prognosis depends on the four clinical entities recognized: indolent form, form associated with hematologic disorder, aggressive SMCD and mast cell leukemia; leukemic transformation with mast cell involvement is characterized by rapid progression of disease with a survival time less than 1 year
Oncogenesis
clinical features of malignant hematopoietic cell growth are influenced by the time, the location of c-kit mutative events, and the number of associated lesions.
Entity name
Small Cell Lung cancer (SCLC)
Disease
KIT overexpression is found in 70% of SCLC patients. Co-expression ofKIT and SCF has been found to create an autocrine loop. The prognostic value of KIT expression is not clear.
Entity name
Testicular Carcinoma
Disease
Activating mutations in KIT exon 17 is found in about 25% of seminomas. Often Asp-816 is replaced with a Val or His residue.
Entity name
Melanoma
Disease
KIT is important for the development of melanocytes. The about 80% of melanomas contain BRAF mutations, but a subset contain activating KITmutations. Interestingly in acral melanomas (affecting foot soles or palms) there is a higher frequency of tumors with activating KIT mutations (20-25% of cases). Examples of KIT mutations found in melanoma are L576P (in exon 11) and K642E (in exon 13). Mutation in position 816 (in exon 17) has also been observed but is not so frequent occurring.
Entity name
Acute Myeloid Leukemia
Disease
KIT expression can be found in about 85% of AML cells. KIT activation can occur by different mechanisms: 1) co-expression of SCF causing an autocrine loop 2) activating mutations in exon 17 affecting Asp-816 or Asn-822. Interestingly, KIT mutations occurs primarily in a subset of leukemias containing inv(16) or t(8;21), so-called core factor binding AML. Apart from exon 17 mutations, also internal tandem duplications in exon 11 have been described.
Prognosis
Presence of D816V mutation in KIT is a poor prognostic factor.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 9027509 | 1997 | Sequence analysis of two genomic regions containing the KIT and the FMS receptor tyrosine kinase genes. | Andre C et al |
| 10660321 | 2000 | C-kit mutations in core binding factor leukemias. | Beghini A et al |
| 16908931 | 2006 | Somatic activation of KIT in distinct subtypes of melanoma. | Curtin JA et al |
| 7529964 | 1995 | Novel mutations and deletions of the KIT (steel factor receptor) gene in human piebaldism. | Ezoe K et al |
| 10554798 | 1999 | c-kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia. | Gari M et al |
| 9438854 | 1998 | Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. | Hirota S et al |
| 23073628 | 2012 | Stem cell factor receptor/c-Kit: from basic science to clinical implications. | Lennartsson J et al |
| 9990072 | 1999 | Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. | Longley BJ Jr et al |
| 8589724 | 1996 | Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. | Longley BJ et al |
| 10702394 | 2000 | KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. | Lux ML et al |
| 10665649 | 1999 | C-kit gene abnormalities in gastrointestinal stromal tumors (tumors of interstitial cells of Cajal. | Sakurai S et al |
| 10362788 | 1999 | Activating c-kit gene mutations in human germ cell tumors. | Tian Q et al |
| 1377810 | 1992 | Cloning and structural analysis of the human c-kit gene. | Vandenbark GR et al |
| 15948115 | 2005 | Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. | Willmore-Payne C et al |
| 20457136 | 2010 | Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. | Woodman SE et al |
Other Information
Locus ID:
NCBI: 3815
MIM: 164920
HGNC: 6342
Ensembl: ENSG00000157404
Variants:
dbSNP: 3815
ClinVar: 3815
TCGA: ENSG00000157404
COSMIC: KIT
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000157404 | ENST00000288135 | P10721 |
| ENSG00000157404 | ENST00000288135 | A0A024RDA0 |
| ENSG00000157404 | ENST00000412167 | P10721 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA10804 | imatinib | Chemical | LabelAnnotation, VariantAnnotation, VipGene | associated | PD | 11526490 | |
| PA151958383 | Gastrointestinal Stromal Tumors | Disease | MultilinkAnnotation, VipGene | associated | 19248971 | ||
| PA162372840 | sunitinib | Chemical | MultilinkAnnotation | associated | 19248971 | ||
| PA166169917 | midostaurin | Chemical | LabelAnnotation | associated | |||
| PA29391 | HOXB4 | Gene | MultilinkAnnotation | associated | 17253940 | ||
| PA29444 | HRAS | Gene | Pathway | associated | 28362716 | ||
| PA30196 | KRAS | Gene | Pathway | associated | 28362716 | ||
| PA31768 | NRAS | Gene | Pathway | associated | 28362716 | ||
| PA33147 | PDGFRA | Gene | MultilinkAnnotation | associated | 24531699 | ||
| PA7000 | sorafenib | Chemical | Pathway | associated | 28362716 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 35855563 | 2024 | Elevated c-kit expression in failed autologous arteriovenous fistulas in end-stage renal disease patients. | 0 |
| 38178783 | 2024 | Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors. | 1 |
| 38408285 | 2024 | KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape. | 0 |
| 35855563 | 2024 | Elevated c-kit expression in failed autologous arteriovenous fistulas in end-stage renal disease patients. | 0 |
| 38178783 | 2024 | Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors. | 1 |
| 38408285 | 2024 | KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape. | 0 |
| 35245395 | 2023 | KIT D816V is dimerization-independent and activates downstream pathways frequently perturbed in mastocytosis. | 0 |
| 36323507 | 2023 | KIT genetic alterations in breast cancer. | 2 |
| 36413413 | 2023 | Low c-Kit expression identifies primitive, therapy-resistant CML stem cells. | 0 |
| 36879550 | 2023 | KIT A502_Y503 duplication mutation serves as a potential and universal target for neoantigen peptide in Chinese GIST patients. | 0 |
| 36959556 | 2023 | Receptor tyrosine kinase C-kit promotes a destructive phenotype of FLS in osteoarthritis via intracellular EMT signaling. | 1 |
| 37113064 | 2023 | Comparison of circulating tumor DNA between African American and Caucasian patients with metastatic castrate-resistant prostate cancer post-abiraterone and/or enzalutamide. | 3 |
| 37174705 | 2023 | Clorfl86/RHEX Is a Negative Regulator of SCF/KIT Signaling in Human Skin Mast Cells. | 3 |
| 37336986 | 2023 | c-Kit signaling potentiates CAR T cell efficacy in solid tumors by CD28- and IL-2-independent co-stimulation. | 4 |
| 37377752 | 2023 | Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557-558 Deletion Mutations. | 2 |
Citation
Lars Rönnstrand ; Johan Lennartsson
KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog)
Atlas Genet Cytogenet Oncol Haematol. 2015-11-01
Online version: http://atlasgeneticsoncology.org/gene/127
Historical Card
2000-06-01 KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) by Lidia Larizza,Alessandro Beghini Affiliation
Division of Translational Cancer Research and, Lund Stem Cell Center, Lund University, Lund, Sweden. [email protected], Ludwig Institute for Cancer Research, Uppsala, Sweden
1998-09-01 KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) by Lidia Larizza,Alessandro Beghini Affiliation
Division of Translational Cancer Research and, Lund Stem Cell Center, Lund University, Lund, Sweden. [email protected], Ludwig Institute for Cancer Research, Uppsala, Sweden
