RAF/MAP kinase cascade PIP3 activates AKT signaling PathwayStep5286 PathwayStep5287 PathwayStep5288 PathwayStep5289 PathwayStep5290 PathwayStep5291 PathwayStep5292 PathwayStep5293 PathwayStep5294 PathwayStep5295 PathwayStep5296 PathwayStep5297 PathwayStep5298 PathwayStep5299 PathwayStep5300 PathwayStep5302 PathwayStep5301 PathwayStep5309 PathwayStep5307 PathwayStep5308 PathwayStep5305 PathwayStep5306 PathwayStep5303 PathwayStep5304 PathwayStep5312 PathwayStep5311 PathwayStep5310 PathwayStep5321 PathwayStep5322 Interaction of Src family kinases with p-KIT Activation of RAC1 Phosphorylation and activation of VAV1 Synthesis of PIP3 from PIP2 by PI3K Direct recruitment of PI3K to p-KIT Autophosphorylation of KIT Phosphorylation of SHP2 by SFKs SHP2 interacts with p-KIT GRB2:SOS interacts with p-KIT Phosphorylation of p-KIT on Y900 by Src kinases Dimerization of KIT upon SCF binding Processing of SCF isoform 1 Interaction of KIT and sSCF Dimerization of sSCF Disassociation and translocation of STATs to the nucleus Dimerization of STATs Phosphorylation of STATs GRB2 is indirectly recruited to p-KIT through SHP2 Phosphorylation of GAB2 by SFKs Indirect recruitment of GAB2 to p-KIT Activation of RAS by p-KIT bound SOS1 Indirect recruitment of PI3K to KIT via p(Y)-GAB2 Interaction of other adapter proteins with p-KIT Interaction of other tyrosine kinases with p-KIT Phosphorylation of JAK2 JAK2 binds to p-KIT Recruitment of STATs PTP-RO interacts with p-c-Kit complex Signaling by SCF-KIT Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed15526160 Pubmed16475976 Pubmed16483568 Pubmed17350321 Pubmed19540337 Pubmed2004790 Pubmed7688988 Reactome Database ID Release 431433557 Reactome, http://www.reactome.org ReactomeREACT_111040 Reviewed: Rönnstrand, L, 2011-08-22 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, Rönnstrand 2004, Lennartsson and Rönnstrand 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 (Rönnstrand 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, Rönnstrand 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. Regulation of KIT signaling PathwayStep3897 PathwayStep3857