Early signaling pathways activated by c-Kit in hematopoietic cells

Abstract

c-Kit is a receptor tyrosine kinase that binds stem cell factor (SCF). Structurally, c-Kit contains five immunoglobulin-like domains extracellularly and a catalytic domain divided into two regions by a 77 amino acid insert intracellularly. Studies in white spotting and steel mice have shown that functional SCF and c-Kit are critical in the survival and development of stem cells involved in hematopoiesis, pigmentation and reproduction. Mutations in c-Kit are associated with a variety of human diseases. Interaction of SCF with c-Kit rapidly induces receptor dimerization and increases in autophosphorylation activity. Downstream of c-Kit, multiple signal transduction components are activated, including phosphatidylinositol-3-kinase, Src family members, the JAK/STAT pathway and the Ras-Raf-MAP kinase cascade. Structure-function studies have begun to address the role of these signaling components in SCF-mediated responses. This review will focus on the biochemical mechanism of action of SCF in hematopoietic cells.

Mouse splice mutant generation from ENU-treated ES cells—A gene-driven approach

“…3G), as is known to be the case for heterozygous Kit mutations that affect the kinase function of the encoded receptor [18,21]. In line with this, the deletion of exon 18 together with the associated frameshift erases a significant portion of the Kit proteinTs second kinase domain [22]. The function of the Kit protein may be further compromised in our mutant by NMD-mediated destabilization of the altered transcript as shown at the ES cell level (Fig.…”

Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease

“…Indeed, from 1 to 9 weeks post-lesion, we found a strong increase in SCF expression, restricted to the site of stem cell engraftment within the striatum. SCF is known to activate its receptor, c-kit, stimulating receptor autophosphorylation and downstream signaling pathways that involve phosphatidylinositol-3-kinase, Src, JAK/STAT and/or MAP kinases (Linnekin, 1999;Wandzioch et al, 2004). c-kit is A, B) or CD11b (red in C, D) in Vehicle/DMEM animals (A, C) or in 4-week QA-lesioned animals (QA/DMEM group; B, D).…”

KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway

“…Signal transducer and activator (STAT) proteins have been implicated in oncogenic signaling by KIT and other receptor tyrosine kinase proteins (Frank 1999;Linnekin 1999). We previously reported expression of STAT1 and STAT3, but not STAT5, in most primary GIST, although STAT1 and STAT3 activation varied considerably in these tumors (Duensing et al, 2004).…”

“…Ligand-mediated activation of wild-type KIT by stem cell factor has been shown to activate PLCg (Linnekin 1999), and PLCg activation might regulate protein kinase C (PKC) signaling through provision of PKC cofactors. We therefore evaluated the effects of PLCg inhibition on phosphorylation of the highly GISTspecific PKC family member, PKCy.…”