KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog)

2015-11-01   Lars Rönnstrand  , Johan Lennartsson  

Identity

HGNC
KIT
LOCATION
4q12
IMAGE
Atlas Image
LEGEND
KIT (4q12) - Courtesy Mariano Rocchi
LOCUSID
3815
ALIAS
C-Kit,CD117,MASTC,PBT,SCFR
FUSION GENES
Show Gene Fusions

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.

Homology

with CSF-1R, PDGFRB, PDGFRA, and FLT3.
Atlas Image
Loss-of-function mutations.
Atlas Image
Gain-of-function mutations.

Mutations

Note

See figures Loss-of-function mutations and Gain-of-function mutations.

Implicated in

Entity name
Piebaldism
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
Systemic Mast Cell Disease (SMCD)
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 IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 3815
MIM: 164920
HGNC: 6342
Ensembl: ENSG00000157404

Variants:

dbSNP: 3815
ClinVar: 3815
TCGA: ENSG00000157404
COSMIC: KIT

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000157404ENST00000288135P10721
ENSG00000157404ENST00000288135A0A024RDA0
ENSG00000157404ENST00000412167P10721

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Hematopoietic cell lineageKEGGko04640
MelanogenesisKEGGko04916
Acute myeloid leukemiaKEGGko05221
Cytokine-cytokine receptor interactionKEGGhsa04060
Hematopoietic cell lineageKEGGhsa04640
MelanogenesisKEGGhsa04916
Pathways in cancerKEGGhsa05200
Acute myeloid leukemiaKEGGhsa05221
EndocytosisKEGGko04144
EndocytosisKEGGhsa04144
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Central carbon metabolism in cancerKEGGhsa05230
Central carbon metabolism in cancerKEGGko05230
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
Regulation of KIT signalingREACTOMER-HSA-1433559
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factorsREACTOMER-HSA-8864260
TFAP2 (AP-2) family regulates transcription of growth factors and their receptorsREACTOMER-HSA-8866910
RET signalingREACTOMER-HSA-8853659
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224

Protein levels (Protein atlas)

Not detected
Low
Medium
High
cerebral cortex
cerebellum
hippocampus
caudate
thyroid gland
parathyroid gland
adrenal gland
nasopharynx
bronchus
lung
oral mucosa
salivary gland
esophagus
stomach 1
stomach 2
duodenum
small intestine
colon
rectum
liver
gallbladder
pancreas
kidney
urinary bladder
testis
epididymis
seminal vesicle
prostate
vagina
ovary
fallopian tube
endometrium 1
endometrium 2
cervix, uterine
placenta
breast
heart muscle
smooth muscle
skeletal muscle
soft tissue 1
soft tissue 2
adipose tissue
skin 1
skin 2
appendix
spleen
lymph node
tonsil
bone marrow

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA10804imatinibChemicalLabelAnnotation, VariantAnnotation, VipGeneassociatedPD11526490
PA151958383Gastrointestinal Stromal TumorsDiseaseMultilinkAnnotation, VipGeneassociated19248971
PA162372840sunitinibChemicalMultilinkAnnotationassociated19248971
PA166169917midostaurinChemicalLabelAnnotationassociated
PA29391HOXB4GeneMultilinkAnnotationassociated17253940
PA29444HRASGenePathwayassociated28362716
PA30196KRASGenePathwayassociated28362716
PA31768NRASGenePathwayassociated28362716
PA33147PDGFRAGeneMultilinkAnnotationassociated24531699
PA7000sorafenibChemicalPathwayassociated28362716

References

Pubmed IDYearTitleCitations
358555632024Elevated c-kit expression in failed autologous arteriovenous fistulas in end-stage renal disease patients.0
381787832024Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors.1
384082852024KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.0
358555632024Elevated c-kit expression in failed autologous arteriovenous fistulas in end-stage renal disease patients.0
381787832024Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors.1
384082852024KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.0
352453952023KIT D816V is dimerization-independent and activates downstream pathways frequently perturbed in mastocytosis.0
363235072023KIT genetic alterations in breast cancer.2
364134132023Low c-Kit expression identifies primitive, therapy-resistant CML stem cells.0
368795502023KIT A502_Y503 duplication mutation serves as a potential and universal target for neoantigen peptide in Chinese GIST patients.0
369595562023Receptor tyrosine kinase C-kit promotes a destructive phenotype of FLS in osteoarthritis via intracellular EMT signaling.1
371130642023Comparison of circulating tumor DNA between African American and Caucasian patients with metastatic castrate-resistant prostate cancer post-abiraterone and/or enzalutamide.3
371747052023Clorfl86/RHEX Is a Negative Regulator of SCF/KIT Signaling in Human Skin Mast Cells.3
373369862023c-Kit signaling potentiates CAR T cell efficacy in solid tumors by CD28- and IL-2-independent co-stimulation.4
373777522023Whole-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/meetings/img/favicon/favicon-32x32.png

Historical Card

2000-06-01 KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) by  Lidia Larizza,Alessandro Beghini 

Division of Translational Cancer Research and, Lund Stem Cell Center, Lund University, Lund, Sweden. lars.ronnstrand@med.lu.se, 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 

Division of Translational Cancer Research and, Lund Stem Cell Center, Lund University, Lund, Sweden. lars.ronnstrand@med.lu.se, Ludwig Institute for Cancer Research, Uppsala, Sweden