KIT_HUMAN » Mast/stem cell growth factor receptor Kit

KIT_HUMAN » Mast/stem cell growth factor receptor Kit
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cytoplasmic side
KIT_HUMAN » Mast/stem cell growth factor receptor Kit » SCFR; Piebald trait protein;PBT; Proto-oncogene c-Kit;Tyrosine-protein kinase Kit;p145 c-kit;v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog;
Hydrophobic Thickness 38.0 ± 2.8 Å
Tilt Angle 3 ± 2°
ΔGtransfer -53.4 kcal/mol
ΔGfold -23.2 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, Reactome, HMDB
Topology Out
TM Segments 518-548 (518-550)
Pathways

Acute myeloid leukemia (KEGG)

Cytokine-cytokine receptor interaction (KEGG)

Endocytosis (KEGG)

Hematopoietic cell lineage (KEGG)

Immune System (Reactome)

Melanogenesis (KEGG)

Pathways in cancer (KEGG)

PI3K-Akt signaling pathway (KEGG)

Signal Transduction (Reactome)

PDB 2ec8 (1-519), 3g0e (544-693, A=754-935), 1t45 (547-693), 4u0i (563-693, A=754-935), 1t46 (565-693), 2e9w (A/B=26-514), 3g0f (A/B=544-693, A/B=754-935), 1pkg (A/B=549-935), 4hvs (A=551-934), 4k94 (C=308-518), 4k9e (C=308-518), 2vif (P=564-574)
OPM none
Complexes

SCF:KIT_HUMAN

KIT:KIT_HUMAN

Interactions

CSF2R, Complex: CSF2R:KIT, PubMed

EPOR, Complex: EPOR:KIT, PubMed

IL3RB, Complex: KIT:IL3RB, PubMed

IL7RA, Complex: KIT:IL7RA, PubMed

KIT, Complex: Homodimer of mast/stem cell growth factor receptor Kit, PDBID: 1PKG

PGFRA, Complex: PGFRA:KIT, PubMed

PTPRJ, Complex: KIT:PTPRJ

PTPRO, Complex: KIT:PTPRO, PubMed

PTPRU, Complex: KIT:PTPRU, PubMed

SCF, Complex: KIT:SCF, PDBID: 2e9w

Domains

AA: 216-305, PDBID: 2E9W, Subunit A, Seq Identity:100%, Immunoglobulin domain

AA: 589-924, PDBID: 1PKG, Subunit A, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for KIT_HUMAN » Mast/stem cell growth factor receptor Kit
FUNCTION: Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.

CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

ENZYME REGULATION: Present in an inactive conformation in the absence of bound ligand. KITLG/SCF binding leads to dimerization and activation by autophosphorylation on tyrosine residues. Activity is down-regulated by PRKCA-mediated phosphorylation on serine residues. Inhibited by imatinib/STI-571 (Gleevec) and sunitinib; these compounds maintain the kinase in an inactive conformation.

SUBUNIT: Monomer in the absence of bound KITLG/SCF. Homodimer in the presence of bound KITLG/SCF, forming a heterotetramer with two KITLG/SCF molecules. Interacts (via phosphorylated tyrosine residues) with the adapter proteins GRB2 and GRB7 (via SH2 domain), and SH2B2/APS. Interacts (via C-terminus) with MPDZ (via the tenth PDZ domain). Interacts (via phosphorylated tyrosine residues) with PIK3R1 and PIK3 catalytic subunit. Interacts (via phosphorylated tyrosine) with CRK (isoform Crk-II), FYN, SHC1 and MATK/CHK (via SH2 domain). Interacts with LYN and FES/FPS. Interacts (via phosphorylated tyrosine residues) with the protein phosphatases PTPN6/SHP-1 (via SH2 domain), PTPN11/SHP-2 (via SH2 domain) and PTPRU. Interacts with PLCG1. Interacts with DOK1 and TEC.

TISSUE SPECIFICITY: Isoform 1 and isoform 2 are detected in spermatogonia and Leydig cells. Isoform 3 is detected in round spermatids, elongating spermatids and spermatozoa (at protein level). Widely expressed. Detected in the hematopoietic system, the gastrointestinal system, in melanocytes and in germ cells.

INDUCTION: Up-regulated by cis-retinoic acid in neuroblastoma cell lines.

DISEASE: Piebald trait (PBT) OMIM: Autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. disease is caused by mutations affecting the gene represented in this entry.

DISEASE: Gastrointestinal stromal tumor (GIST) OMIM: Common mesenchymal neoplasms arising in the gastrointestinal tract, most often in the stomach. They are histologically, immunohistochemically, and genetically different from typical leiomyomas, leiomyosarcomas, and schwannomas. Most GISTs are composed of a fairly uniform population of spindle-shaped cells. Some tumors are dominated by epithelioid cells or contain a mixture of spindle and epithelioid morphologies. Primary GISTs in the gastrointestinal tract commonly metastasize in the omentum and mesenteries, often as multiple nodules. However, primary tumors may also occur outside of the gastrointestinal tract, in other intra-abdominal locations, especially in the omentum and mesentery. entry is involved in disease pathogenesis.

DISEASE: Testicular germ cell tumor (TGCT) OMIM: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. Note=The gene represented in this entry may be involved in disease pathogenesis.

DISEASE: Leukemia, acute myelogenous (AML) OMIM: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. Note=The gene represented in this entry is involved in disease pathogenesis. Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.

MISCELLANEOUS: Numerous proteins are phosphorylated in response to KIT signaling, but it is not evident to determine which are directly phosphorylated by KIT under in vivo conditions.

UniProt features for KIT_HUMAN » Mast/stem cell growth factor receptor Kit
SIGNAL 1 25 Potential.
CHAIN 26 976 Mast/stem cell growth factor receptor Kit.
DOMAIN 27 112 Ig-like C2-type 1.
DOMAIN 121 205 Ig-like C2-type 2.
DOMAIN 212 308 Ig-like C2-type 3.
DOMAIN 317 410 Ig-like C2-type 4.
DOMAIN 413 507 Ig-like C2-type 5.
DOMAIN 589 937 Protein kinase.
REGION 568 570 Important for interaction with phosphotyrosine-binding proteins.
ACT_SITE 792 792 Proton acceptor (By similarity).
SITE 936 936 Important for interaction with phosphotyrosine-binding proteins.
DISULFID 58 97
DISULFID 136 186
DISULFID 151 183
DISULFID 233 290
DISULFID 428 491
Amino Acid Sequence for KIT_HUMAN » Mast/stem cell growth factor receptor Kit
MRGARGAWDF LCVLLLLLRV QTGSSQPSVS PGEPSPPSIH PGKSDLIVRV GDEIRLLCTD PGFVKWTFEI LDETNENKQN EWITEKAEAT NTGKYTCTNK HGLSNSIYVF VRDPAKLFLV DRSLYGKEDN DTLVRCPLTD PEVTNYSLKG CQGKPLPKDL RFIPDPKAGI MIKSVKRAYH RLCLHCSVDQ EGKSVLSEKF ILKVRPAFKA VPVVSVSKAS YLLREGEEFT VTCTIKDVSS SVYSTWKREN SQTKLQEKYN SWHHGDFNYE RQATLTISSA RVNDSGVFMC YANNTFGSAN VTTTLEVVDK GFINIFPMIN TTVFVNDGEN VDLIVEYEAF PKPEHQQWIY MNRTFTDKWE DYPKSENESN IRYVSELHLT RLKGTEGGTY TFLVSNSDVN AAIAFNVYVN TKPEILTYDR LVNGMLQCVA AGFPEPTIDW YFCPGTEQRC SASVLPVDVQ TLNSSGPPFG KLVVQSSIDS SAFKHNGTVE CKAYNDVGKT SAYFNFAFKG NNKEQIHPHT LFTPLLIGFV IVAGMMCIIV MILTYKYLQK PMYEVQWKVV EEINGNNYVY IDPTQLPYDH KWEFPRNRLS FGKTLGAGAF GKVVEATAYG LIKSDAAMTV AVKMLKPSAH LTEREALMSE LKVLSYLGNH MNIVNLLGAC TIGGPTLVIT EYCCYGDLLN FLRRKRDSFI CSKQEDHAEA ALYKNLLHSK ESSCSDSTNE YMDMKPGVSY VVPTKADKRR SVRIGSYIER DVTPAIMEDD ELALDLEDLL SFSYQVAKGM AFLASKNCIH RDLAARNILL THGRITKICD FGLARDIKND SNYVVKGNAR LPVKWMAPES IFNCVYTFES DVWSYGIFLW ELFSLGSSPY PGMPVDSKFY KMIKEGFRML SPEHAPAEMY DIMKTCWDAD PLKRPTFKQI VQLIEKQISE STNHIYSNLA NCSPNRQKPV VDHSVRINSV GSTASSSQPL LVHDDV