Signaling by SCF-KIT (Homo sapiens)

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2, 34, 40, 61, 72...3181552, 27, 4010, 304, 11, 17, 19, 37...6, 37, 56, 627, 16, 25, 53, 603, 15, 69, 7918, 36, 40, 601, 2822, 4620, 25, 609, 338126, 294325, 41, 45, 54, 6037, 4881, 8392, 32, 39, 671330, 5797121, 60, 70711, 63, 75, 8068, 71, 788, 14, 42, 45, 50...9, 33, 74cytosolnucleoplasmTyrosine kinasesKITLG-1(26-190) CHEK1 FYN FYN YES1 KITLG-1(26-190) p-7Y-KIT p-7Y-KIT ATPp-Y546,Y584-PTPN11 STAT5A LYN SOS1 JAK2 GRB10 KITLG-1KITLG-1(26-190) PIK3R1 SOCS1 KITLG-1(26-190) p-7Y-KIT KITLG-1(26-190) SFKs:p-8Y-KIT:sSCFdimer:p-8Y-KITLYN SRC-1 KITLG-1(26-190) p-Y1007-JAK2 CBLSTAT1 SHP2:SFKs:p-KIT:sSCFdimer:p-KITFYN CHEK1 FYN KITLG-1(26-190) LCK SRC-1 JAK2:SFKS:p-KITcomplexp-7Y-KIT RAC1 SOCS1P13K:p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexFES FYN KITLG-1(26-190) GTP SRC-1 SH2B3PIK3CA GRB2-1 KITLG-1(26-190) SRC-1 STAT1 p-7Y-KIT SRC-1 FYN FYN YES1 ADPYES1 p-Y546,Y584-PTPN11 YES1 LYN KITLG-1(26-190) GRAP PTPRU p-Y694-STAT5A GAB2:GRB2:p-SHP2:p-KIT complexGRB7 LYN KRAS STAT5B RAC1:GDPp-Y629-SH2B2 p-7Y-KIT KITLG-1(26-190)ATPp-7Y-KIT ADPLYN KITLG-1(26-190) ADPLYN p-7Y-KIT p-Y546,Y584-PTPN11 SRC-1 LCK KITLG-1(26-190) SOCS1:p-KIT complexLCK GRB2-1 GRB2-1 p21 RAS:GTPGTPLCK NRAS KITLG-1(26-190) YES1 Src family tyrosinekinases (SFKs)PRKCA YES1 p-Y629-SH2B2 p-7Y-KIT p-Y142,Y160,Y174-VAV1 YES1 GTPKITLG-1(26-190) FYN LCK YES1 LCK p-Y-GAB2 Grb2:SOS:p-c-Kit/p-APS:p-c-Kit complexPIK3R2 p-Y705-STAT3 YES1 p-7Y-KIT p-7Y-KIT:sSCFdimer:p-7Y-KITLCK p-Y699-STAT5B SRC-1 FYN Adapter proteinsFYN SH2B2 FYN KIT YES1 sSCF dimerp-Y699-STAT5B p-STAT dimersp-KIT (S741,746):PKCalphaKIT:sSCF dimerCMA1 PI(3,4,5)P3PTPN6PIK3R3 SRC-1 PTPN11 p-7Y-KIT STAT3 GRB10 GDPTyrosinekinases:p-KITcomplexp-Y1007-JAK2 p-Y701-STAT1-1 LCK p-Y546,Y584-PTPN11 LCK p-Y-GAB2 LCK PIK3R3 p-JAK2:SFKs:p-KITcomplex:STATsKITLG-1(192-273)KITLG-1(26-190) GRB2-1p-APS dimer:p-KITcomplexp-7Y-KIT KITLG-1(26-190) LYN PIK3CA GDP p-7Y-KIT SRC-1 GAB2 LYN STAT5B FYN KIT ADPSH2B3 LYN SRC-1 MMP9 KITLG-1(26-190) GRB2-1:SOS1LYN PI(4,5)P2GRAP2 p-7Y-KIT p-7Y-KIT LCK RAC1 PTPRUSTAT5A KITLG-1(26-190) GRB2-1 p-Y629-SH2B2 APSdimer:p-c-Kit:SFKscomplexATPLCK PIK3CA PTPN6 GAB2PI3K:p-KIT:sSCFdimer:p-KITGRB2:SOS1:p-KITcomplexADPCBL:Grb2/p-APS:p-c-Kit complexp-Y694-STAT5A GRAP LCK SRC-1 FER SRC-1 KRAS PIK3R1 KITLG-1(26-190) LCK p-SHP2:p-KIT complexKITLG-1(26-190) YES1 FYN YES1 p-Y701-STAT1-1 STATsPIK3R2 LYN VAV1YES1 SRC-1 FER p-7Y-KIT KIT:sSCF dimer:KITLNK:p-7Y-KIT:sSCFdimer:p-7Y-KITGRB7 FYN p-JAK2:SFKs:p-KITcomplex:p-STATdimersGDP YES1 RAC1:GTPSRC-1 KITLG-1(26-190) PI3K alphaLYN HRAS KITLG-1(26-190) GRB2-1 ATPPRKCAKIT SOCS6:p-c-Kit:sSCFdimer:p-c-KitYES1 GRB2-1 p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexLCK KITLG-1(26-190) GTP ATPSOS1 PI(3,4,5)P3 p21 RAS:GDPAdapterproteins:p-KITcomplexp-7Y-KIT HRAS CBL p-7Y-KIT PIK3R1 ADPKITPTPRO:KITLCK APS dimerLYN SRC-1 p-JAK2:SFKs:p-KITcomplex:p-STATsFYN YES1 SH2B2 FYN GDPJAK2LYN SOS1 KITLG-1(26-190) RAF/MAP kinasecascadeSRC-1 FYN p-Y1007-JAK2 ADPp-Y1007-JAK2 Endopeptidases forSCF processingp-S741,S746-KIT p-7Y-KIT p-JAK2:SFKs:p-KITcomplexSOCS6 LCK LYN p-Y694-STAT5A GRAP2 LYN p-7Y-KIT SOCS6ATPGRB2:p-SHP2:p-KITcomplexSOS1 YES1 p-8Y-KIT LCK p-7Y-KIT p-7Y-KIT GRB2-1 ADPKITLG-1(26-190) YES1 p-Y546,Y584-PTPN11 FES p-Y699-STAT5B SRC-1 GRB2-1 PIP3 activates AKTsignalingNRAS p-Y701-STAT1-1 p-VAV1:PIP3p-7Y-KIT STAT3 SRC-1 KITLG-1(26-190) TEC FYN KITLG-1(26-190) PIK3R2 SFKs:p-KIT complexp-Y705-STAT3 ATPLYN TEC LYN p-7Y-KIT p-Y705-STAT3 PTPN11KITLG-1(26-190) p-7Y-KIT PIK3R3 KITLG-1(26-190) SHP-1:p-c-Kitcomplex5, 4712, 13, 23, 24, 35...


Description

Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Ronnstrand 2004, Lennartsson and Ronnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Ronnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Ronnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 1433557
Reactome-version 
Reactome version: 63
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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Bibliography

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History

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CompareRevisionActionTimeUserComment
101337view11:22, 1 November 2018ReactomeTeamreactome version 66
100875view20:56, 31 October 2018ReactomeTeamreactome version 65
100416view19:30, 31 October 2018ReactomeTeamreactome version 64
99966view16:14, 31 October 2018ReactomeTeamreactome version 63
99520view14:49, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99162view12:41, 31 October 2018ReactomeTeamreactome version 62
93973view13:49, 16 August 2017ReactomeTeamreactome version 61
93574view11:27, 9 August 2017ReactomeTeamreactome version 61
87186view08:05, 19 July 2016EgonwOntology Term : 'signaling pathway' added !
86676view09:23, 11 July 2016ReactomeTeamreactome version 56
83115view10:00, 18 November 2015ReactomeTeamVersion54
81455view12:59, 21 August 2015ReactomeTeamVersion53
76929view08:20, 17 July 2014ReactomeTeamFixed remaining interactions
76634view12:00, 16 July 2014ReactomeTeamFixed remaining interactions
75964view10:02, 11 June 2014ReactomeTeamRe-fixing comment source
75667view10:57, 10 June 2014ReactomeTeamReactome 48 Update
75022view13:53, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74666view08:43, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
APS

dimer:p-c-Kit:SFKs

complex
ComplexR-HSA-205257 (Reactome)
APS dimerComplexR-HSA-1433305 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Adapter

proteins:p-KIT

complex
ComplexR-HSA-1433538 (Reactome)
Adapter proteinsComplexR-HSA-1433422 (Reactome)
CBL ProteinP22681 (Uniprot-TrEMBL)
CBL:Grb2/p-APS:p-c-Kit complexComplexR-HSA-205200 (Reactome)
CBLProteinP22681 (Uniprot-TrEMBL)
CHEK1 ProteinO14757 (Uniprot-TrEMBL)
CMA1 ProteinP23946 (Uniprot-TrEMBL)
Endopeptidases for SCF processingComplexR-HSA-1433401 (Reactome)
FER ProteinP16591 (Uniprot-TrEMBL)
FES ProteinP07332 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
GAB2:GRB2:p-SHP2:p-KIT complexComplexR-HSA-1433545 (Reactome)
GAB2ProteinQ9UQC2 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRAP ProteinQ13588 (Uniprot-TrEMBL)
GRAP2 ProteinO75791 (Uniprot-TrEMBL)
GRB10 ProteinQ13322 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GRB2:SOS1:p-KIT complexComplexR-HSA-205202 (Reactome)
GRB2:p-SHP2:p-KIT complexComplexR-HSA-1433549 (Reactome)
GRB7 ProteinQ14451 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Grb2:SOS:p-c-Kit/p-APS:p-c-Kit complexComplexR-HSA-1433400 (Reactome)
HRAS ProteinP01112 (Uniprot-TrEMBL)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
JAK2:SFKS:p-KIT complexComplexR-HSA-1433493 (Reactome)
JAK2ProteinO60674 (Uniprot-TrEMBL)
KIT ProteinP10721 (Uniprot-TrEMBL)
KIT:sSCF dimer:KITComplexR-HSA-205208 (Reactome)
KIT:sSCF dimerComplexR-HSA-205166 (Reactome)
KITLG-1(192-273)ProteinP21583-1 (Uniprot-TrEMBL)
KITLG-1(26-190) ProteinP21583-1 (Uniprot-TrEMBL)
KITLG-1(26-190)ProteinP21583-1 (Uniprot-TrEMBL)
KITLG-1ProteinP21583-1 (Uniprot-TrEMBL)
KITProteinP10721 (Uniprot-TrEMBL)
KRAS ProteinP01116 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LNK:p-7Y-KIT:sSCF dimer:p-7Y-KITComplexR-HSA-1562562 (Reactome)
LYN ProteinP07948 (Uniprot-TrEMBL)
MMP9 ProteinP14780 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
P13K:p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexComplexR-HSA-1562561 (Reactome)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K alphaComplexR-HSA-198379 (Reactome)
PI3K:p-KIT:sSCF dimer:p-KITComplexR-HSA-205177 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PRKCA ProteinP17252 (Uniprot-TrEMBL)
PRKCAProteinP17252 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6ProteinP29350 (Uniprot-TrEMBL)
PTPRO:KITComplexR-HSA-1433419 (Reactome)
PTPRU ProteinQ92729 (Uniprot-TrEMBL)
PTPRUProteinQ92729 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GDPComplexR-HSA-445010 (Reactome)
RAC1:GTPComplexR-HSA-442641 (Reactome)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
SFKs:p-8Y-KIT:sSCF dimer:p-8Y-KITComplexR-HSA-1472120 (Reactome)
SFKs:p-KIT complexComplexR-HSA-205271 (Reactome)
SH2B2 ProteinO14492 (Uniprot-TrEMBL)
SH2B3 ProteinQ9UQQ2 (Uniprot-TrEMBL)
SH2B3ProteinQ9UQQ2 (Uniprot-TrEMBL)
SHP-1:p-c-Kit complexComplexR-HSA-205181 (Reactome)
SHP2:SFKs:p-KIT:sSCF dimer:p-KITComplexR-HSA-205267 (Reactome)
SOCS1 ProteinO15524 (Uniprot-TrEMBL)
SOCS1:p-KIT complexComplexR-HSA-1433442 (Reactome)
SOCS1ProteinO15524 (Uniprot-TrEMBL)
SOCS6 ProteinO14544 (Uniprot-TrEMBL)
SOCS6:p-c-Kit:sSCF dimer:p-c-KitComplexR-HSA-1470001 (Reactome)
SOCS6ProteinO14544 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
STAT1 ProteinP42224 (Uniprot-TrEMBL)
STAT3 ProteinP40763 (Uniprot-TrEMBL)
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
STATsComplexR-HSA-1433551 (Reactome)
Src family tyrosine kinases (SFKs)ComplexR-HSA-211064 (Reactome)
TEC ProteinP42680 (Uniprot-TrEMBL)
Tyrosine

kinases:p-KIT

complex
ComplexR-HSA-205201 (Reactome)
Tyrosine kinasesComplexR-HSA-1433353 (Reactome)
VAV1ProteinP15498 (Uniprot-TrEMBL)
YES1 ProteinP07947 (Uniprot-TrEMBL)
p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexComplexR-HSA-1562560 (Reactome)
p-7Y-KIT ProteinP10721 (Uniprot-TrEMBL)
p-7Y-KIT:sSCF dimer:p-7Y-KITComplexR-HSA-205310 (Reactome)
p-8Y-KIT ProteinP10721 (Uniprot-TrEMBL)
p-APS dimer:p-KIT complexComplexR-HSA-1433276 (Reactome)
p-JAK2:SFKs:p-KIT complex:STATsComplexR-HSA-1433527 (Reactome)
p-JAK2:SFKs:p-KIT

complex:p-STAT

dimers
ComplexR-HSA-1469999 (Reactome)
p-JAK2:SFKs:p-KIT complex:p-STATsComplexR-HSA-1470000 (Reactome)
p-JAK2:SFKs:p-KIT complexComplexR-HSA-1433552 (Reactome)
p-KIT (S741,746):PKC alphaComplexR-HSA-1433473 (Reactome)
p-S741,S746-KIT ProteinP10721 (Uniprot-TrEMBL)
p-SHP2:p-KIT complexComplexR-HSA-1433530 (Reactome)
p-STAT dimersComplexR-HSA-1566924 (Reactome)
p-VAV1:PIP3ComplexR-HSA-1433526 (Reactome)
p-Y-GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
p-Y1007-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-Y142,Y160,Y174-VAV1 ProteinP15498 (Uniprot-TrEMBL)
p-Y546,Y584-PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
p-Y629-SH2B2 ProteinO14492 (Uniprot-TrEMBL)
p-Y694-STAT5A ProteinP42229 (Uniprot-TrEMBL)
p-Y699-STAT5B ProteinP51692 (Uniprot-TrEMBL)
p-Y701-STAT1-1 ProteinP42224-1 (Uniprot-TrEMBL)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)
sSCF dimerComplexR-HSA-1433307 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-1433418 (Reactome)
ADPArrowR-HSA-1433454 (Reactome)
ADPArrowR-HSA-1433488 (Reactome)
ADPArrowR-HSA-1433506 (Reactome)
ADPArrowR-HSA-1433508 (Reactome)
ADPArrowR-HSA-1433514 (Reactome)
ADPArrowR-HSA-1433542 (Reactome)
ADPArrowR-HSA-1470009 (Reactome)
ADPArrowR-HSA-1472121 (Reactome)
ADPArrowR-HSA-205289 (Reactome)
APS

dimer:p-c-Kit:SFKs

complex
ArrowR-HSA-205319 (Reactome)
APS

dimer:p-c-Kit:SFKs

complex
R-HSA-1433506 (Reactome)
APS

dimer:p-c-Kit:SFKs

complex
mim-catalysisR-HSA-1433506 (Reactome)
APS dimerR-HSA-205319 (Reactome)
ATPR-HSA-1433418 (Reactome)
ATPR-HSA-1433454 (Reactome)
ATPR-HSA-1433488 (Reactome)
ATPR-HSA-1433506 (Reactome)
ATPR-HSA-1433508 (Reactome)
ATPR-HSA-1433514 (Reactome)
ATPR-HSA-1433542 (Reactome)
ATPR-HSA-1470009 (Reactome)
ATPR-HSA-1472121 (Reactome)
ATPR-HSA-205289 (Reactome)
Adapter

proteins:p-KIT

complex
ArrowR-HSA-1433501 (Reactome)
Adapter proteinsR-HSA-1433501 (Reactome)
CBL:Grb2/p-APS:p-c-Kit complexArrowR-HSA-205244 (Reactome)
CBLR-HSA-205244 (Reactome)
Endopeptidases for SCF processingmim-catalysisR-HSA-1433374 (Reactome)
GAB2:GRB2:p-SHP2:p-KIT complexArrowR-HSA-205234 (Reactome)
GAB2:GRB2:p-SHP2:p-KIT complexR-HSA-1433454 (Reactome)
GAB2:GRB2:p-SHP2:p-KIT complexmim-catalysisR-HSA-1433454 (Reactome)
GAB2R-HSA-205234 (Reactome)
GDPArrowR-HSA-1433415 (Reactome)
GDPArrowR-HSA-1433471 (Reactome)
GRB2-1:SOS1R-HSA-205286 (Reactome)
GRB2-1R-HSA-1433428 (Reactome)
GRB2:SOS1:p-KIT complexArrowR-HSA-205286 (Reactome)
GRB2:SOS1:p-KIT complexmim-catalysisR-HSA-1433471 (Reactome)
GRB2:p-SHP2:p-KIT complexArrowR-HSA-1433428 (Reactome)
GRB2:p-SHP2:p-KIT complexR-HSA-205234 (Reactome)
GTPR-HSA-1433415 (Reactome)
GTPR-HSA-1433471 (Reactome)
Grb2:SOS:p-c-Kit/p-APS:p-c-Kit complexR-HSA-205244 (Reactome)
JAK2:SFKS:p-KIT complexArrowR-HSA-1433451 (Reactome)
JAK2:SFKS:p-KIT complexR-HSA-1433418 (Reactome)
JAK2:SFKS:p-KIT complexmim-catalysisR-HSA-1433418 (Reactome)
JAK2R-HSA-1433451 (Reactome)
KIT:sSCF dimer:KITArrowR-HSA-205231 (Reactome)
KIT:sSCF dimer:KITR-HSA-205289 (Reactome)
KIT:sSCF dimer:KITmim-catalysisR-HSA-205289 (Reactome)
KIT:sSCF dimerArrowR-HSA-205321 (Reactome)
KIT:sSCF dimerR-HSA-205231 (Reactome)
KITLG-1(192-273)ArrowR-HSA-1433374 (Reactome)
KITLG-1(26-190)ArrowR-HSA-1433374 (Reactome)
KITLG-1(26-190)R-HSA-1433395 (Reactome)
KITLG-1R-HSA-1433374 (Reactome)
KITR-HSA-1433423 (Reactome)
KITR-HSA-1433508 (Reactome)
KITR-HSA-205231 (Reactome)
KITR-HSA-205321 (Reactome)
LNK:p-7Y-KIT:sSCF dimer:p-7Y-KITArrowR-HSA-1562640 (Reactome)
P13K:p(Y)-GAB2:GRB2:p-SHP2:p-KIT complexArrowR-HSA-1562641 (Reactome)
PI(3,4,5)P3ArrowR-HSA-1433514 (Reactome)
PI(3,4,5)P3R-HSA-1433542 (Reactome)
PI(4,5)P2R-HSA-1433514 (Reactome)
PI3K alphaR-HSA-1562641 (Reactome)
PI3K alphaR-HSA-205262 (Reactome)
PI3K:p-KIT:sSCF dimer:p-KITArrowR-HSA-205262 (Reactome)
PI3K:p-KIT:sSCF dimer:p-KITmim-catalysisR-HSA-1433514 (Reactome)
PRKCAR-HSA-1433508 (Reactome)
PRKCAmim-catalysisR-HSA-1433508 (Reactome)
PTPN11R-HSA-205238 (Reactome)
PTPN6R-HSA-205306 (Reactome)
PTPRO:KITArrowR-HSA-1433423 (Reactome)
PTPRUR-HSA-1433423 (Reactome)
R-HSA-1433374 (Reactome) SCF exists as two alternatively spliced variants, a soluble form and a membrane-bound form differing in one exon (exon 6). Both isoforms are initially membrane bound with an extracellular domain, a transmembrane segment and an intracellular region. The longer isoform is rapidly cleaved to generate a 165 aa soluble protein knows as sSCF. The SCF transcript that lacks exon 6 encodes a glycoprotein that remains membrane-bound (mSCF). Both mSCF and sSCF are bioactive but different in their efficacy in c-kit activation.
Proteases including matrix metalloprotease-9 (Heissig et al., 2002), Chymase-1 (Longley et al., 1997) and several members of the ADAMs family (Kawaguchi et al, 2007; Amour et al, 2002; Chesneau et al, 2003; Mohan et al, 2002; Roghani et al, 1999; Zou et al, 2004) have been suggested to have a role in the processing of sSCF.
R-HSA-1433395 (Reactome) sSCF exists as noncovalently associated homodimer composed of two monomers interacting head-to-head to form an elongated, slightly bent dimer. Dimerization of sSCF is a dynamic process and it may play a regulatory role in the dimerization and activation of KIT (Zhang et al, 2000; Philo et al, 1996).
R-HSA-1433410 (Reactome) SOCS1 has been identified as a KIT binding partner from the yeast two-hybrid system (Sepulveda et al, 1999). SOCS1 expression is induced upon KIT activation. It associates with KIT via its SH2 domain. SOCS1 does not inhibit KIT kinase activity directly, instead it binds to GRB2 and VAV1, and selectively inhibits SCF-induced proliferation, while not effecting survival signal (Sepulveda et al, 1999). It has been proposed that SOCS1 may interrupt signal transduction pathways downstream of JAK2 (Sepulveda et al, 1999).
R-HSA-1433415 (Reactome) Vav1, once activated by PIP3 binding and phosphorylation by Src kinases, stimulates the GDP/GTP exchange activity of Rac. Vav1 is selective for Rac and catalyses exchange of bound GDP for GTP.
R-HSA-1433418 (Reactome) SCF induces rapid and transient autophosphorylation of JAK2 bound to c-KIT. JAKs bound to activated, dimerized receptors cross-phosphorylate and thereby activate each other. Multiple phosphorylation sites have been identified in JAK2 (tyrosines 221, 570, 868, 966, 972, 1007 and 1008 ) of which phosphorylation of tyrosine 1007 is essential for kinase activity (Feng et al 1997, Argetsinger et al. 2004, 2010). Tyrosine 1007 is in the activation loop and phosphorylation allows access of the catalytic loop to the ATP in the ATP binding domain. Of all the predicted phoshorylation sites only the critical tyrosine 1007 is represented in the reaction.
R-HSA-1433423 (Reactome) Tyrosine phosphatase PTPRO associates constitutively with c-Kit independently of SCF stimulation. PTPRO undergoes phosphorylation upon SCF stimulation. The PTPRO binding site on c-Kit and the molecular mechanism by which c-Kit signaling is regulated by PTPRO have not been determined.
R-HSA-1433428 (Reactome) GRB2 can be recruited indirectly to KIT through SHP2 (Tauchi et al. 1994). Y279, Y304, Y546 and Y584 (usually referred to as Y542 and Y580 in literature based on the SHP2 short isoform) are the potential sites of SHP2 tyrosyl phosphorylation and that Y546 is the major GRB2 binding site (Feng, et al. 1993, Araki, et al. 2003). This brings Grb2:SOS1 into proximity with the plasma membrane, where it can activate Ras.
R-HSA-1433451 (Reactome) Janus kinase 2 (JAK2) plays an important role in SCF induced proliferation (Radosevic et al. 2004). JAK2 was observed to pre-associate with KIT, with increased association after SCF stimulation of KIT (Weiler et al. 1996).
R-HSA-1433454 (Reactome) GAB2 bound to GRB2 on KIT is then phosphorylated on a number of tyrosine residues through the action of Src family kinases (SFKs).
R-HSA-1433456 (Reactome) Activation of KIT mediates the recruitment of and association with STAT1alpha, STAT3, STAT5A and STAT5B (Deberry et al. 1997, Brizzi et al. 1999, Rönnstrand 2004).
R-HSA-1433471 (Reactome) Once recruited to the membrane in response to c-Kit stimulation, Son of sevenless (SOS1) activates the small GTPase protein Ras. SOS1 is a dual specificity guanine nucleotide exchange factor (GEF) that regulates both Ras and Rho family GTPases. SOS1 activates Ras by binding which induces a conformational change that causes the exchange of GDP with GTP. Ras proteins are membrane-bound GTPases that regulate crucial cellular processes such as growth, proliferation and differentiation. Active Ras-GTP stimulates multiple effector proteins such as Raf-1, which induce a variety of cellular responses, including initiation of mitogen activated protein kinase (MAPK) cascade signaling.
R-HSA-1433488 (Reactome) Following association with KIT, Tauchi et al. had observed phosphorylation of SHP2 (Tauchi et al. 1994). Tyrosine residues Y546 and Y584 (usually referred to as Y542 and Y580 in literature based on the short isoform) are the major sites of SHP2 tyrosyl phosphorylation. Src family kinases (SFKs) are candidates for this phosphorylation (Araki et al. 2003). The phosphorylated tyrosine residues on SHP2 can recruit the adapter protein GRB2 (Tauchi et al. 1994), but it is unclear whether GRB2 binding to SHP2 is important for KIT mediated SHP2 signaling or whether the effect of SHP2 on the RAS/ERK pathway goes through its catalytic activity.
R-HSA-1433501 (Reactome) Adapter proteins GADS, GRAP, GRB7 and GRB10 interact with activated KIT (Liu & McGlade 1998, Feng et al. 1996, Thömmes et al. 1999, Jahn et al. 2002).
R-HSA-1433506 (Reactome) APS bound to KIT is phosphorylated by tyrosine kinases in response to SCF stimulation (Wollberg et al, 2003). The C-terminal tyrosine 629 may be the target site of phosphorylation in APS (Wakioka et al, 1999).
R-HSA-1433508 (Reactome) Protein kinase C (PKC) alpha phosphorylates and regulates the activity of several receptor tyrosine kinases including KIT. PKC alpha is involved in a negative feedback loop regulating SCF induced proliferation by phosphorylating and inhibiting the kinase activity of KIT (Blume-Jensen et al. 1994, 1995). PKC alpha phosphorylates KIT on S741 and S746 of the kinase insert (Blume-Jensen et al. 1995). This serine phosphorylation inhibits KIT kinase activity and reduces the capacity of multiple SH2 containing signaling components to associate with KIT (Linnekin 1999).
R-HSA-1433514 (Reactome) PI3 kinases catalyze the production of phosphatidylinositol-3, 4, 5-triphosphate (PIP3) by phosphorylating phosphatidylinositol-4, 5-bisphosphate (PIP2). PIP3 bound to the inner lipid bilayer of the plasma membrane promotes the recruitment and activation of AKT. Active AKT subsequently phosphorylates the pro-apoptotic factor Bad at Ser136 which leads to it binding 14-3-3 protein and sequestering from the anti-apoptotic molecules Bcl-XL therby reducing antiapoptotic events and promoting cell survival. The alternative route for c-Kit mediated survival is through AKT-mediated phosphorylation and incativation of the forkhead transcription factor (FoxO3a) (Engstrom et al, 2003; Lennartson et al , 2005).
R-HSA-1433542 (Reactome) The Src and PI3-kinase signaling pathways converge to activate Rac1 and JNK after c-Kit activation, promoting mast cell proliferation but not for suppression of apoptosis (Timokhina et al. 1998). PI3K and Src are considered mediators of c-Kit induced Rac1 activation via the guanine nucleotide exchange factor (GEF) VAV1. Stimulation of c-Kit receptor results in rapid tyrosine phosphorylation of VAV1 (Timokhina et al. 1998).
VAV1 exists in an auto-inhibitory state folded in such a way as to inhibit the GEF activity of its Dbl homology domain (DH) domain. PI3K is thought to modulate the activation of VAV1 by influencing its degree of tyrosine phosphorylation and its recruitment to membrane. VAV1 is recruited to membrane by binding to PtdIns(3,4,5)P3 (PIP3) and this interaction relieves an intramolecular interaction between pleckstrin homology (PH) and DH domains, thus facilitating tyrosine phosphorylation on Y174 and so further opening of the DH/PH domains, binding of Rac-GDP and catalysis (Welch et al, 2003). In VAV1, tyrosine 174 (Y174) binds to the DH domain and inhibits its GEF activity. Src kinases phosphorylate this Y174 and this causes the tyrosine to move away from the DH domain thereby reliving the auto-inhibition.
R-HSA-1470009 (Reactome) JAK2 activation results in the phosphorylation and activation of STAT1alpha, STAT3, STAT5A and STAT5B (Deberry et al. 1997, Brizzi et al. 1999, Ning et al. 2001, Ronnstrand 2004). STAT family members can be activated by JAK kinases, receptor tyrosine kinases or SFKs. LYN kinase has been identified to have role in SCF-induced phosphorylation of STAT3 (Shivakrupa & Linnekin 2005).
R-HSA-1470010 (Reactome) Phosphorylation on a tyrosine residues immediately distal to the SH2 domain induces STATs homo- or heterodimerization through phosphotyrosine-SH2 interactions.
R-HSA-1470011 (Reactome) SOCS6 protein interacts with the phosphorylated Y568 in the juxtamembrane domain of c-Kit following SCF-stimulated tyrosine phosphorylation. Binding of SOCS6 to Y568 may mask this docking site for Src family kinases and this may inhibit the phosphorylation of p38 and ERK. This negatively regulates c-Kit receptor proliferation signal but not SCF-induced chemotaxis (Bayle et al. 2004, Zadjali et al 2011). Binding of SOCS6 mediates recruitment of elongin B and C to form a ubiquitin E3 ligase complex that leads to ubiquitination of KIT and its degradation (Zadjali et al 2011).
R-HSA-1470012 (Reactome) After dimerization STAT dimers release from the receptor complex and migrate to the nucleus for DNA binding. STAT5s/STAT1alpha heterodimeric complexes specifically recognize beta-casein promoter region (PIE) (Brizzi et al. 1999). c-Kit dependent JAK/STAT activation is associated with the growth and differentiation of fetal liver haematopoietic progenitor cells (Rönnstrand 2004, Reber et al. 2006).
R-HSA-1472121 (Reactome) Src family of tyrosine kinases phosphorylate KIT on Y900 located in the second part of the tyrosine kinase domain. This phosphorylated tyrosine acts as a docking site for p85alpha regulatory subunit of PI3K and the adapter protein CRKII. CRKII does not interact directly with KIT but is recruited indirectly by binding to p85alpha subunit of PI3K. Thus, in this case the p85 subunit acts as an adapter between KIT and CRKII, and not to recruit PI3-kinase. (Lennartsson et al. 2003).
R-HSA-1562640 (Reactome) The adaptor protein LNK with its SH2 domain binds to the juxtamembrane domain (amino acids 544-577) of KIT on Y568 and inhibit the downstream signalling (Gueller et al. 2008).
R-HSA-1562641 (Reactome) Phosphorylated GAB2 recruits the p85 subunit of the PI3K complex and activates the PI3K/AKT pathway. This is one of two mechanisms described for the recruitment of PI3K to KIT.
R-HSA-205205 (Reactome) Binding of SCF to KIT induces the activation and rapid increase in kinase activity of multiple Src family kinases (SFK), including Src, Lck, Tec, Fyn, and Lyn (Timokhina et al. 1998, Krystal et al. 1998, Linnekin et al. 1997, Lennartsson et al. 1999, Tang et al. 1994, Samayawardhena et al. 2007). The tyrosine residues Y568 and Y570 in KIT juxtamembrane region are involved in the association of SFKs (Price et al. 1997).
SFKs recruited to KIT induce proliferation and chemotaxis in primary hematopoietic progenitor cells or bone marrow derived mast cells (O'Laughlin-Bunner et al. 2001). SCF activated SFKs also mediate a critical signal for lymphocyte development (Agosti et al. 2004). Timokhina et al. demonstrated that Src kinase and PI3-kinase signalling pathways converge to activate Rac1 and JNK after SCF stimulation in BMMC, promoting cell proliferation (Timokhina et al., 1998, Reber et al. 2006 ).
R-HSA-205231 (Reactome) Binding of the SCF dimer to KIT rapidly triggers KIT dimerization and autophosphorylation. It is thought that one SCF dimer binds simultaneously to two KIT monomers. The fourth Ig-like domain of KIT contains the dimerisation site; deletion of this domain completely abolishes KIT dimerisation and subsequent downstream signaling (Edling et al. 2007, Blechman et al. 1995). KIT dimerization is a crucial initial step in the SCF signal transduction process.
R-HSA-205234 (Reactome) The scaffolding adapter GAB2 plays a role in KIT dependent PI3K/AKT activation. GAB2 interacts with KIT indirectly via the adapter protein GRB2 which is bound to KIT on phosphorylated Y703 and Y936 (Sun et al. 2008, Yu et al. 2006).
R-HSA-205238 (Reactome) SHP2 is a protein tyrosine phosphatase (PTP) with two NH2-terminal SH2 domains, a PTP domain, a -COOH tail with two tyrosyl phosphorylation sites at Y546 and Y584, and an interposed proline-rich domain. SHP2 binds to activated KIT on tyrosine-568 in the juxtamembrane region, which also constitutes the docking site for a number of other signal transduction molecules, such as SFKs, Csk homologous kinase (CHK), CBL, LNK and Adapter protein with PH and SH2 domains (APS) (Kozlowski et al. 1998, Price et al. 1997, Gueller et al. 2008).
R-HSA-205244 (Reactome) The phosphotyrosine residue in APS creates a putative binding site for CBL. CBL is an ubiquitin E3 ligase that attaches ubiquitin to KIT leading to KIT's ubiquitination followed by internalization and degradation. GRB2 in addition to its role in positive signaling via RAS/ERK pathway also mediates negative regulation of KIT by recruiting CBL (Sun et al, 2007). CBL has also been shown to bind directly to both Y568 and Y936 in KIT (Masson et al. 2006). CBL bound to KIT ubiquitinates KIT and targets it to lysosomal degradation (Masson et al. 2006)
R-HSA-205262 (Reactome) The regulatory subunit (p85) of PI3K interacts directly with phosphorylated Y721 of KIT via one of its SH2 domains. This binding leads to the activation of the catalytic domain (p110) of PI3K. SCF-induced PI3K recruitment mediates AKT activation through phospholipids at the membrane and to subsequent phosphorylation of the pro-apoptotic factor Bad as well as Fox3a.
PI3K activation mediates SCF-induced cell proliferation, survival, differentiation, adhesion, secretion and actin cytoskeletal organization.
R-HSA-205286 (Reactome) GRB2 is an adapter protein with one SH2 domain and two SH3 domains. It exists in part as a preformed complex with the RAS GDP/GTP exchanger SOS. GRB2 with its SH2 domain binds directly to activated KIT on autophosphorylated sites Y703 and Y936 (Thommes et al. 1999). GRB2 can also be recruited indirectly to KIT by binding KIT downstream signal transduction molecules such as SHP 2, SHC1, GAB1 and GAB2 (Rönnstrand 2004, Linnekin 1999). GRB2:SOS complex bound to KIT then activates the small GTPase protein RAS. It should be noted that not all GRB2 interactions with KIT involves an activation of RAS, but it can also act as an adapter protein for recruiting both GAB2 (Sun et al. 2008) and CBL (Sun et al. 2007) to KIT.
R-HSA-205289 (Reactome) The cytoplasmic domain of KIT contains a bipartite kinase domain separated by 77 residues. The first part of the catalytic domain contains the ATP binding region while the second part contains an activation loop. Both parts of the domain have a number of possible autophosphorylation sites. In contrast to many other tyrosine kinases, autophosphorylation of the activation loop does not seem to be involved in the activation of the kinase activity nor it is required for full kinase activity (DiNitto et al. 2010). Instead, phosphorylation sites in the juxtamembrane region are important for activation of the kinase activity. The dimerized KIT acts as both enzyme and substrate for itself and autophosphorylates these specific tyrosine residues with in the kinases domains in trans as well as tyrosine residues outside the kinase domain. The resulting phosphotyrosine residues serve as docking sites for a number of signal transduction molecules containing Src-homology 2 (SH2) and phosphotyrosine-binding (PTB) domains. A majority of the autophosphorylation sites reside outside the kinase domain.
R-HSA-205306 (Reactome) The protein tyrosine phosphatase SHP-1 negatively regulates KIT signaling through binding to phosphorylated Y570. It is unclear whether SHP1 directly dephosphorylates KIT or elicits dephosphorylation of the receptor indirectly by dephosphorylating and inhibiting cytosolic PTKs that act on KIT. SHP-1 may also compete with and displace SFKs or other proteins that dock to phosphorylated Y570 (Kozlowski et al, 1998).
R-HSA-205319 (Reactome) APS adapter protein has been identified as a KIT binding partner using yeast two-hybrid screening. APS contains a PH domain and an SH2 domain. The SH2 domain interacts with c-Kit phosphotyrosine residues Y568 and Y936 (Wollberg et al. 2003).
R-HSA-205321 (Reactome) Two human isoforms of KIT have been identified, resulting from alternative splicing. They are characterized by the presence or absence of a tetrapeptide sequence (GNNK 510-513 aa) in the extracellular part of the juxtamembrane region and designated GNNK+ (Kit) or GNNK- (KitA) (Piao et al. 1994). The isoforms are co-expressed in most tisuues, with the GNNK- form predominating (Reith et al. 1991). No difference in ligand affinity was observed (Caruana et al. 1999).
KIT belongs to the type III tyrosine kinase receptor family, with five extracellular immunoglobulin (Ig)-like domains, a single transmembrane region, an inhibitory cytoplasmic juxtamembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment and a cytoplasmic tail (Mol et al. 2003).
Signaling by KIT occurs following SCF binding. SCF homodimers binds to the first three Ig-like domains of KIT in the regions between aa L104-D122 and R146-D153 (Mendiaz et al. 1996, Matous et al. 1996) which leads to dimerization which is further stabilized by Ig-like domains 3-4 (Yuzawa et al., 2007).