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Growth factors and the extracellular matrix have been shown to fulfill vital developmental roles in many embryonic systems. Our hypothesis is that a developmental role played by the extracellular matrix in sea urchins may be the binding of a PDGF-like growth factor to promote signaling activity. We report here that anti-human PDGF-B antibodies and anti-human TGF-[alpha] antibodies immunoprecipitated specific proteins isolated from Lytechinus embryos. Addition of these antibodies to Lytechinus embryos inhibited gastrulation and spiculogenesis. The embryos are sensitive to the antibodies from the four-cell through the hatching blastula stages, which suggests that the TGF-[alpha]-like and PDGF-like ligands are required for the early differentiation of the gut and spicules. We present evidence that the PDGF-like growth factor depends on the extracellular matrix for signaling activity. Synthetic peptides representing the heparan sulfate proteoglycan binding sequence on human PDGF-B were added to Lytechinus embryo cultures to compete for binding sites with the endogenous PDGF-like growth factor. The experimental peptide inhibited gastrulation and caused radially arranged multiple spicules to form. Development was unaffected by a control peptide. These studies support our hypothesis and suggest that TGF-[alpha]-like and PDGF-like growth factors induce signaling events required for sea urchin gastrulation and spiculogenesis and suggest that an extracellular matrix-associated PDGF-like growth factor is involved in differentiation along the oral-aboral axis.

The effect of platelet-derived growth factor (PDGF) on low density lipoprotein (LDL) gene expression reveals differential induction and growth response. Induction by isoforms on expression of c-myc gene and DNA synth esis showed the PDGF-homodimer to be more effective in contrast to the PDGF-AA homodimer in human skin fibroblast and NIH 3T3 cells. Secondary messenger pathways for PDGF activation of c-myc gene differ from that of LDL receptor gene.

The tyrosine platelet-derived growth factor receptor-beta (PDGFR-beta) balances migration-promoting and migration-suppressing activities to maintain chemotaxis toward the PDGF-BB homodimer. Specific tyrosines are mapped to reveal the mechanism involved in regulating chemotaxis. Phosphatidylinositol-3-OH kinase promotes chemotaxis in association with PDGFR-beta while Ras-GTPase-activating protein inhibits migration.

Boota, Ahmad, Bruce Johnson, Kee-L Lee, Michelle A. Blaskovich, Shang-Xi Liu, Valerian E. Kagan, Andrew Hamilton, Bruce Pitt, Said M. Sebti, and Paul Davies. Prenyltransferase inhibitors block superoxide production by pulmonary vascular smooth muscle. Am. J. Physiol. Lung Cell. Mol. Physiol. 278: L329-L334, 2000.--We recently showed that the farnesyltransferase inhibitor FTI-277 blocks. interleukin 1[Beta] (IL-1[Beta])-induced nitric oxide production in pulmonary vascular smooth muscle cells (SMC), whereas the geranylgeranyltransferase inhibitor GGTI-298 enhances this effect. Here we show that IL-I[Beta] and platelet-derived growth factor (PDGF) stimulate superoxide production by pulmonary vascular SMC and that this effect is blocked by both FTI-277 and GGTI-298, suggesting that farnesylated and geranylgeranylated proteins are required for superoxide production. We also show that FTI-277 and GGTI-298 block superoxide production stimulated by constitutively active mutant H-Ras. Furthermore, superoxide production by IL-1[Beta], PDGF factor, and constitutively activated Ras is blocked by diphenyleneiodonium, implicating NAD(P)H oxidase as the generating enzyme. Given the role of oxidant radicals in vascular reactivity and injury, the action of both FTI-277 and GGTI-298 in suppressing superoxide generation by an inflammatory cytokine as well as by a potent smooth muscle mitogen may be therapeutically useful. farnesyltransferase; geranylgeranyltransferase; Ras; platelet-derived growth factor; interleukin-[Beta]