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.

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).

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)

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).

SCF induced proliferation is negatively regulated by various proteins including SHP1, PKC, CBL, SOCS1, SOCS6 and LNK.

Mastinib is a class II tyrosine kinase inhibitor that targets mutant and wild-type FGFR3, PDGFR and c-KIT (Dubreuil, 2009). Masitinib, like imatinib, is effective in inhibiting the activity of juxtamembrane mutant forms of KIT, but is ineffective against many of the mutations in the activation loop and ATP-binding cleft of the receptor (Dubreuil, 2009; Serrano et al, 2019; reviewed in Demetri, 2011).

Masitinib is a multi-kinase inhibitor that targets mutant and wild-type FGFR3, PDGFR and c-KIT (Dubreuil, 2009). It is currently in Phase II clinical trials for multiple myeloma (NCT00866138).

A broad specificity ATP-competitive inhibitor of FGF-, VEGF-, PDGF- and KIT receptors that is in Phase I and II clinical trials for treatment of gastric, breast and endometrial cancers.

A Novartis tyrosine kinase inhibitor with activity against multiple tyrosine kinase receptors including FGFRs, VEGFRs, PDGFRs, KIT, FLT3 and CSFR. TKI258 is in Phase II clinical trials for advanced breast cancer in patients with and without FGFR1 amplification (NCT00958971), for endometrial cancer with WT or activated FGFR2 mutants (NCT01379534), for relapsed myeloma with and without the t4:14 FGFR3 translocation/amplification (NCT01058434), and in bladder cancer in cases where archived material is available to check for correlation with FGFR3 mutation status (NCT00790426).

Mast/stem cell growth factor receptor Kit

Tandutinib is reported as a fms-related tyrosine kinase 3 (FLT3) inhibitor, although it has almost identical IC50s for PDGRFβ and KIT.

A pyrrolopyridine that is 5-chloro-1H-pyrrolo[2,3-b]pyridine which is substituted by a [6-({[6-(trifluoromethyl)pyridin-3-yl]methyl}amino)pyridin-3-yl]methyl group at position 3. It is a potent multi-targeted receptor tyrosine kinase inhibitor of CSF-1R, KIT, and FLT3 (IC50 of 20 nM, 10 nM and 160 nM, respectively). Approved by the FDA for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT).