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

2015-11-01 Lars Rönnstrand , Johan Lennartsson Affiliation

Identity

HGNC

KIT

LOCATION

4q12

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.

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

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 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)

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

Pathway	Source	External ID
Cytokine-cytokine receptor interaction	KEGG	ko04060
Hematopoietic cell lineage	KEGG	ko04640
Melanogenesis	KEGG	ko04916
Acute myeloid leukemia	KEGG	ko05221
Cytokine-cytokine receptor interaction	KEGG	hsa04060
Hematopoietic cell lineage	KEGG	hsa04640
Melanogenesis	KEGG	hsa04916
Pathways in cancer	KEGG	hsa05200
Acute myeloid leukemia	KEGG	hsa05221
Endocytosis	KEGG	ko04144
Endocytosis	KEGG	hsa04144
PI3K-Akt signaling pathway	KEGG	hsa04151
PI3K-Akt signaling pathway	KEGG	ko04151
Ras signaling pathway	KEGG	hsa04014
Rap1 signaling pathway	KEGG	hsa04015
Rap1 signaling pathway	KEGG	ko04015
Central carbon metabolism in cancer	KEGG	hsa05230
Central carbon metabolism in cancer	KEGG	ko05230
Disease	REACTOME	R-HSA-1643685
Diseases of signal transduction	REACTOME	R-HSA-5663202
PI3K/AKT Signaling in Cancer	REACTOME	R-HSA-2219528
Constitutive Signaling by Aberrant PI3K in Cancer	REACTOME	R-HSA-2219530
Immune System	REACTOME	R-HSA-168256
Adaptive Immune System	REACTOME	R-HSA-1280218
Signaling by the B Cell Receptor (BCR)	REACTOME	R-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)	REACTOME	R-HSA-1168372
PIP3 activates AKT signaling	REACTOME	R-HSA-1257604
Negative regulation of the PI3K/AKT network	REACTOME	R-HSA-199418
Innate Immune System	REACTOME	R-HSA-168249
DAP12 interactions	REACTOME	R-HSA-2172127
DAP12 signaling	REACTOME	R-HSA-2424491
RAF/MAP kinase cascade	REACTOME	R-HSA-5673001
Fc epsilon receptor (FCERI) signaling	REACTOME	R-HSA-2454202
FCERI mediated MAPK activation	REACTOME	R-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilization	REACTOME	R-HSA-2730905
Cytokine Signaling in Immune system	REACTOME	R-HSA-1280215
Signaling by Interleukins	REACTOME	R-HSA-449147
Interleukin-2 signaling	REACTOME	R-HSA-451927
Interleukin receptor SHC signaling	REACTOME	R-HSA-912526
Interleukin-3, 5 and GM-CSF signaling	REACTOME	R-HSA-512988
Signal Transduction	REACTOME	R-HSA-162582
Signaling by EGFR	REACTOME	R-HSA-177929
GRB2 events in EGFR signaling	REACTOME	R-HSA-179812
SHC1 events in EGFR signaling	REACTOME	R-HSA-180336
GAB1 signalosome	REACTOME	R-HSA-180292
Signaling by Insulin receptor	REACTOME	R-HSA-74752
Insulin receptor signalling cascade	REACTOME	R-HSA-74751
IRS-mediated signalling	REACTOME	R-HSA-112399
SOS-mediated signalling	REACTOME	R-HSA-112412
Signalling by NGF	REACTOME	R-HSA-166520
NGF signalling via TRKA from the plasma membrane	REACTOME	R-HSA-187037
Signalling to ERKs	REACTOME	R-HSA-187687
Signalling to RAS	REACTOME	R-HSA-167044
Signalling to p38 via RIT and RIN	REACTOME	R-HSA-187706
Prolonged ERK activation events	REACTOME	R-HSA-169893
Frs2-mediated activation	REACTOME	R-HSA-170968
ARMS-mediated activation	REACTOME	R-HSA-170984
PI3K/AKT activation	REACTOME	R-HSA-198203
Signaling by PDGF	REACTOME	R-HSA-186797
Downstream signal transduction	REACTOME	R-HSA-186763
Signaling by VEGF	REACTOME	R-HSA-194138
VEGFA-VEGFR2 Pathway	REACTOME	R-HSA-4420097
VEGFR2 mediated cell proliferation	REACTOME	R-HSA-5218921
Signaling by SCF-KIT	REACTOME	R-HSA-1433557
Regulation of KIT signaling	REACTOME	R-HSA-1433559
MAPK family signaling cascades	REACTOME	R-HSA-5683057
MAPK1/MAPK3 signaling	REACTOME	R-HSA-5684996
Signaling by GPCR	REACTOME	R-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPK	REACTOME	R-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	REACTOME	R-HSA-2404192
IGF1R signaling cascade	REACTOME	R-HSA-2428924
IRS-related events triggered by IGF1R	REACTOME	R-HSA-2428928
Signaling by Leptin	REACTOME	R-HSA-2586552
Gene Expression	REACTOME	R-HSA-74160
Generic Transcription Pathway	REACTOME	R-HSA-212436
Developmental Biology	REACTOME	R-HSA-1266738
Axon guidance	REACTOME	R-HSA-422475
NCAM signaling for neurite out-growth	REACTOME	R-HSA-375165
Phospholipase D signaling pathway	KEGG	ko04072
Phospholipase D signaling pathway	KEGG	hsa04072
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	REACTOME	R-HSA-6811558
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	REACTOME	R-HSA-8864260
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	REACTOME	R-HSA-8866910
RET signaling	REACTOME	R-HSA-8853659
Breast cancer	KEGG	ko05224
Breast cancer	KEGG	hsa05224

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	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/meetings/gene-explorer/css/template-nav.css

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. 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 Affiliation

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