Stem Cell Factor Receptor/c-Kit: From Basic Science to Clinical Implications

Abstract

Stem cell factor (SCF) is a dimeric molecule that exerts its biological functions by binding to and activating the receptor tyrosine kinase c-Kit. Activation of c-Kit leads to its autophosphorylation and initiation of signal transduction. Signaling proteins are recruited to activated c-Kit by certain interaction domains (e.g., SH2 and PTB) that specifically bind to phosphorylated tyrosine residues in the intracellular region of c-Kit. Activation of c-Kit signaling has been found to mediate cell survival, migration, and proliferation depending on the cell type. Signaling from c-Kit is crucial for normal hematopoiesis, pigmentation, fertility, gut movement, and some aspects of the nervous system. Deregulated c-Kit kinase activity has been found in a number of pathological conditions, including cancer and allergy. The observation that gain-of-function mutations in c-Kit can promote tumor formation and progression has stimulated the development of therapeutics agents targeting this receptor, e.g., the clinically used inhibitor imatinib mesylate. Also other clinically used multiselective kinase inhibitors, for instance, sorafenib and sunitinib, have c-Kit included in their range of targets. Furthermore, loss-of-function mutations in c-Kit have been observed and shown to give rise to a condition called piebaldism. This review provides a summary of our current knowledge regarding structural and functional aspects of c-Kit signaling both under normal and pathological conditions, as well as advances in the development of low-molecular-weight molecules inhibiting c-Kit function.

Hotspot mutations in common oncogenes are infrequent in nasopharyngeal carcinoma

“…In contrast, KIT E839K was not spontaneously phosphorylated in response to exogenous SCF and thus lacked cell transforming ability (45). KIT phosphorylated mutants could be inhibited by KIT inhibitors such as imatinib and dasatinib (47). These data together with our findings that KIT mutation correlated with poor survival in NPC, suggest that targeting KIT could be a potential therapeutic strategy in the treatment of NPC.…”

SOCS proteins in regulation of receptor tyrosine kinase signaling

“…Overexpression or mutation of RTKs and their aberrant activation of downstream signaling pathways have been linked to the oncogenic transformation, angiogenesis, atherosclerosis, bone disorder, inflammation and diabetes. For example, the epidermal growth factor (EGF) receptor (EGFR) is overexpressed in lung cancer and colon cancer, ERBB2 is overexpressed in certain types of breast cancer, FLT3 is mutated in acute myeloid leukemia and KIT is mutated in mastocytosis [8,9]. The association of RTKs with human diseases has driven the development of novel class of drugs targeting these proteins.…”

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

“…While more mature cells of all lineages gradually shut down KIT expression, mast cells remain dependent on KIT signaling for their entire life-span. KIT activation triggers several signaling pathways, including phosphoinositol 3-kinases (PI3K), Src family kinases and the mitogen-activated-protein-kinase (MAPK), janus kinase/signal transducers and activators of transcription (JAK/STAT) and phospholipase C and D signaling [9]. Gain-of-function mutations of KIT that result in constitutive, ligandindependent signaling cause the human disease mastocytosis [10].…”