Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis.

Abstract

The proto‐oncogene c‐kit is allelic with the murine white spotting (W) locus and encodes a transmembrane protein tyrosine kinase that is structurally related to the receptors for platelet‐derived growth factor (PDGF) and colony‐stimulating factor‐1 (CSF‐1). Recently the ligand for the c‐kit product, stem cell factor (SCF), was identified in both transmembrane and soluble forms. In order to examine the mechanism for receptor activation by SCF and biological properties of the activated c‐kit product, we transfected the wild‐type human c‐kit cDNA into porcine aortic endothelial cells. We found that the receptor was down‐regulated and transmitted a mitogenic signal in response to stimulation with soluble SCF. We also demonstrate that SCF induces dimerization of the c‐kit product in intact cells, and that dimerization of the receptor is correlated with activation of its kinase. Activation of the c‐kit product by SCF was found to induce circular actin reorganization indistinguishable from that mediated by the PDGF beta‐receptor in response to PDGF‐BB. Furthermore, soluble SCF was a potent chemotactic agent for cells expressing the c‐kit product, a property which might be of importance during embryonic development.

Human Stem Cell Factor Dimer Forms a Complex with Two Molecules of the Extracellular Domain of Its Receptor, Kit

“…The 2:2 complex formation clearly provides a mechanism for Kit dimerization, which is known to occur in vivo and to be required for initiation of signal transduction (21,31,51). However, because all of our data is obtained in vitro, we cannot definitely state that such a complex would transmit or initiate biological signaling in vivo, and, as always, there are differences between in vitro and in vivo situations.…”

“…3). 5 Note that reported bell-shaped SCF doseresponse curves (43,51) can be interpreted as being consistent with a lack of cooperativity, i.e. if the binding of a second Kit is not favored relative to binding of the first, Kit molecules will tend to be associated singly with SCF dimers when SCF is in excess over Kit.…”

Actin-dependent Lamellipodia Formation and Microtubule-dependent Tail Retraction Control-directed Cell Migration

“…However, this did not address the issue of whether microtubules may be essential in stimulated ruffle formation. PMA and growth factors are known to be potent stimulators for actin reorganization Blume-Jensen et al, 1991;Vosseller et al, 1997;Timokhina et al, 1998). Melanoma cells treated with PMA showed ruffling and lamellipodium formation in a Rac-dependent manner because ruffling was not observed in cells expressing the dominantnegative form of Rac.…”

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

“…Activation of KIT regulates important cell functions, including proliferation, apoptosis, chemotaxis, and adhesion, and is critical for the development and maintenance of mast cells, hematopoietic stem cells, melanocytes, gametocytes, and interstitial cells of Cajal (ICC), pacemaker cells involved in regulation of the gastrointestinal (GI) tract mobility and autonomous neural transmission. [7][8][9][10][11][12][13][14] PDGFRs are normally activated by platelet-derived growth factors (PDGFs) and expressed on hematopoietic cells, including erythroid and myeloid bone marrow precursor cells, monocytes and megacaryocytes as well as glial cells, endothelial cells, fibroblasts, and osteoblasts. 6 …”