KIT signaling is important in several processes including stem cell maintenance, erythropoiesis, mast cell development, lymphopoiesis, melanogenesis and maintenance of interstitial cell of Cajal (Hirota et al, 1998; Chi et al, 2010). Gain-of-function mutations in KIT have been identified at low frequency in a number of diseases, including AML, melanoma and mast and germ cell tumors, and at higher frequency in gastrointesinal stromal tumors (reviewed in Lennartsson and Roonstrand, 2012; Abbaspour Babaei et al, 2016; Roskoski, 2018).
Activation of the PI3K/mTOR, RAS/MAPK and STAT signaling pathways has been observed downstream of activated extracellular, juxtamembrane and kinase domain mutants of KIT, although downstream signaling has not been studied in great detail in all cases. Activation of these pathways contributes to cellular proliferation, avoidance of apoptosis, and actin cytoskeletal organization (Dunesing et al, 2004; Bauer et al, 2007; Chi et al, 2010; Bosbach et al, 2017; reviewed in Lennartsson and Roonstrand, 2012; Corless et al, 2011).
A number of activating extracellular-, juxtamembrane- and kinase-domain KIT mutants are believed to signal through the RAS/MAP kinase cascade, as assessed by the presence of phospho-ERK1 and 2 (also known as MAPK3 and MAPK1). Although the pathway has not been studied in detail, signaling downstream of KIT mutants likely involves recruitment of GRB2:SOS1, as is the case for the wild-type receptor Frost et al, 2002; Garner et al, 2014; Monsel et al, 2010; Obata et al, 2017; Chi et al, 2010; Ran et al, 2015; Serrano et al, 2015; Zhu et al, 2007; reviewed in Abbaspour Babaei et al, 2016; Lennartsson and Roonstrand, 2012).
Activation of the MAP kinase signaling pathway downstream of oncogenic KIT mutants, as evidenced by the presence of phosphorylated ERK proteins, likely depends on the SOS-mediated nucleotide exchange of GDP for GTP on RAS, as is the case for the wild-type receptor (Frost et al, 2002; Chi et al, 2010; Garner et al, 2014; Monsel et al, 2010; Obata et al, 2017; reviewed in Abbaspour Babaei et al, 2016; Lennartsson and Roonstrand, 2012).