CHARACTERIZATION OF SIGNALLING PATHAYS OF THE PDGF/CSF-1 RECEPTOR

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Alpha and beta platelet-derived growth factor receptors (PDGFR) are encoded by two different genes and are triggered differently by the three dimeric forms of PDGF. The specific functions mediated by the products of the independent PDGF receptor-encoding genes have been investigated. By using a strategy involving introduction of expression vectors for alpha and betaPDGFR cDNAs into a naive hematopoietic cell line (32D), it has been demonstrated that each receptor independently couples with mitogenic signal transduction pathways inherently present in these cells. Both receptors can induce chemotactic responses, inositol phospholipid metabolism and [Ca 2+] mobilization. The human alphaPDGFR, like the betaPDGFR and colony stimulating factor (CSF)-1/c-fms, is interrupted by a kinase insert. In order to define the role of this region, two deletion mutants which lacked 81 (709-790) and 96 (694-790) amino acids of the 104-amino acid kinase insert have been generated. The functional characteristics of these mutants have been compared with the wild-type alphaPDGFR following introduction into the same hematopoietic cell line. Only the small deletion was capable of coupling with the mitogenic signalling pathway, phosphoinositide turnover and chemotactic response, but in a less efficient way. Furthermore, the insertion of the c-fms kinase insert into the large deletion mutant restored the biochemical and biological activities of the alphaPDGFR. These results indicate that alterations in the structural conformation of the kinase domain of the alphaPDGFR affect the multiple functions of this molecule.