| 1. |
- Blume-Jensen, Peter, et al.
(författare)
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Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis
- 1991
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Ingår i: EMBO Journal. - 0261-4189 .- 1460-2075. ; 10:13, s. 4121-4128
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- Heldin, Carl-Henrik, et al.
(författare)
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Platelet-derived growth factor : isoform-specific signalling via heterodimeric or homodimeric receptor complexes
- 1992
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538 .- 1523-1755. ; 41:3, s. 571-574
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Growth factors are polypeptides that are involved in the regulation of cell growth and differentiation, such as, during the embryonal development, in wound healing, in hematopoiesis, in the immune response, as well as in several adverse reactions including malignancies. Several families of structurally-related growth factors are known; new members of these families continue to be discovered and occasionally new families are found. One of the best characterized growth factor family is the platelet-derived growth factor (PDGF) family. PDGF was originally found to be present in the alpha-granules of platelets and to have growth promoting activity for fibroblasts and smooth muscle cells; subsequent studies have shown that PDGF is synthesized by a large number of different normal as well as transformed cell types, and that it acts not only on connective tissue cells but also on other types of cells [reviewed in 1, 2]. The present review summarizes some recent developments in the elucidation of the structural and functional properties of PDGF and PDGF receptors, the mechanism for PDGF signalling at the cellular level and the possible in vivo effects of PDGF.
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| 3. |
- Risau, W, et al.
(författare)
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Platelet-derived growth factor is angiogenic in vivo
- 1992
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Ingår i: Growth Factors. - 0897-7194 .- 1029-2292. ; 7:4, s. 261-266
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- PDGF receptors have recently been found to be expressed in microvascular endothelium in vivo under circumstances of endothelial cell activation and angiogenesis suggesting that PDGF may have a direct effect on endothelial cells. We have tested the angiogenic activity of PDGF-AA and -BB homodimers in the chick chorioallantoic membrane in vivo. PDGF-BB was found to consistently induce an angiogenic response whereas PDGF-AA was less active. Morphological analyses revealed that there was little inflammation associated with this response but an increase in vessel density suggested a direct effect of PDGF on embryonic chorioallantoic endothelial cells. In vitro, PDGF-BB was found to be more potent than PDGF-AA in stimulating the chemotaxis of rat brain capillary endothelial cells. This is consistent with a direct effect of PDGF on endothelial cells. Thus, this novel angiogenic activity of PDGF has implications for several developmental and pathological events in which PDGF, particularly the B-chain, is expressed.
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| 4. |
- Rupp, Eva, et al.
(författare)
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A unique autophosphorylation site in the platelet-derived growth factor alpha receptor from a heterodimeric receptor complex
- 1994
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Ingår i: European Journal of Biochemistry. - 0014-2956 .- 1432-1033. ; 225:1, s. 29-41
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Tidskriftsartikel (refereegranskat)abstract
- The platelet-derived growth factor (PDGF) alpha and beta receptors undergo dimerization as a consequence of ligand binding. Depending on the PDGF isoform (PDGF-AA, -AB or -BB), homodimers or heterodimers of receptors are formed. In this study, we have used transfected porcine aortic endothelial cells, coexpressing cDNAs for the alpha receptor and the beta receptor at comparable levels, to investigate the properties of the alpha beta-heterodimeric receptor complex. PDGF-AB, which mainly induced alpha beta-heterodimeric complexes, was the most efficient isoform for stimulating mitogenicity. Actin reorganization, in the form of circular membrane ruffling and chemotaxis, was induced by PDGF-AB and PDGF-BB, but not by PDGF-AA, thus indicating that the beta receptor in the homodimeric or heterodimeric configuration was required for induction of motility responses. The molecular basis for the apparent receptor dimer-specific properties was examined by analyzing receptor autophosphorylation and phosphorylation of substrates. The alpha receptor was found to be phosphorylated at an additional tyrosine residue, Tyr754, in the heterodimeric complex as compared to the alpha alpha receptor homodimer. Phosphorylation of this tyrosine residue could permit the binding of a specific signal-tranducing protein. A candidate is a 134,000-M(r) protein, which was shown to associate preferentially with the alpha receptor in the heterodimeric receptor complex. It is possible that phosphorylated Tyr754 in the alpha receptor mediates activation of specific signal-tranducing molecules like the 134,000-M(r) substrate, and thereby initiates signal-tranduction pathways from the alpha beta receptor heterodimer, which are distinct from those initiated via homodimeric receptor complexes.
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