Structural and immunological similarities between simian sarcoma virus gene product(s) and human platelet-derived growth factor

Robbins, K C; Antoniades, Harry N.; Devare, S G; Hunkapiller, Michael W.; Aaronson, Stuart A.

doi:10.1038/305605a0

Cited by 328 publications

(141 citation statements)

References 24 publications

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“…Platelet-derived growth factor (PDGF) is a disulfidelinked dimer composed of two polypeptide chains, denoted A and B and represented in vivo by three PDGFs, PDGF-AA, PDGF-AB and PDGF-BB (Robbins et al, 1983;Heldin et al, 1986;Beckmann et al, 1988;Hart et al, 1990;Heldin and Westermark, 1999). These isoforms bind to and activate two structurally related protein tyrosine kinase receptors, PDGFR-a and PDGFR-b.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases

Siegfried

Basak²,

Prichett-Pejic³

et al. 2005

Oncogene

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Platelet-derived growth factor-B (PDGF-B) is important for normal tissue growth and maintenance and its overexpression has been linked to several diseases, including cancer, fibrotic disease and atherosclerosis. Here, we show that synthesized as a precursor, proPDGF-B is converted to a mature form by proteolytic cleavage at two sites and its N-terminal cleavage is a prerequisite for processing at its C-terminus. The first cleavage occurs at residues RGRR 81 k, and the second cleavage close to residues ARPVT 190 , just before the Cterminal amino-acid sequence crucial for PDGF-B retention to cell surface. Cotransfection of a Furin-deficient cell line LoVo-C5 with proPDGF-B and different PC members revealed that Furin, PACE4, PC5, and PC7 are candidate proPDGF-B convertases. This finding is consistent with the in vitro digestions of a synthetic peptide mimicking the cleavage site of proPDGF-B. The processing of proPDGF-B is blocked by site-directed mutagenesis of the RGRR 81 k sequence and by various PC inhibitors. Mutation of the PDGF-A and/or PDGF-B convertase sites, revealed that processing of both A and B chains is required for the formation of mature PDGF-B dimers and that the processing of the B chain controls the level of secreted and matrix-bound PDGF-BB forms. Our findings emphasize the importance of the convertasedirected processing of proPDGF-B at the RGRR 81 k sequence for PDGF-B maturation and secretion. Oncogene (2005) 24, 6925-6935.

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Section: Introductionmentioning

confidence: 99%

Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases

Siegfried

Basak²,

Prichett-Pejic³

et al. 2005

Oncogene

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“…Thus, all possible dimeric combinations of PDGF chains have been found (Figure 1). SSV-transformation is exerted by externalized PDGF-BB The structural homology between p28Ss' and PDGF (Waterfield et al, 1983;Doolittle et al, 1983;Robbins et al, 1983), led to the hypothesis that a PDGF-like growth factor is involved in SSV-transformation. This hypothesis has received support from several subsequent observations.…”

mentioning

confidence: 99%

“…a heterodimer of one A chain and one B chain (Hammacher et al, 1988a). PDGF purified from porcine platelets (Stroobant & Waterfield, 1984), as well as the transforming protein of SSV (Robbins et al, 1983) have been identified as PDGF-BB. Finally, structural analyses of PDGF-like factors purified from the conditioned media of human osteosarcoma (Heldin et al, 1986b) melanoma (Westermark et al, 1986b) and glioma (Hammacher et al, 1986b) cell lines, revealed the existence also of PDGF-AA.…”

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confidence: 99%

Structural and functional aspects of platelet-derived growth factor

Hammacher²,

Nistér³

et al. 1988

Br J Cancer

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Summary The finding that PDGF production is common in normal as well as transformed cells indicate that PDGF has a function in autocrine and paracrine stimulation of cells in several physiological and pathological conditions. The expression of mRNA for the two chains of PDGF are independently regulated. The fact that the different dimeric forms of PDGF have different functional effects, indicate that the cellular response to PDGF may be more complex than previously thought, and may involve binding to more than one receptor. The cellular effects ascribed to PDGF, growth stimulation, ruffling and chemotaxis, seems to be mainly associated with B chain containing dimers. The function of PDGF-AA remains to be elucidated.

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“…The v-sis oncogene contains an env-sis fused open reading frame of 813 nucleotides, potentially encoding a protein of 33 kilodaltons (kDa) (5). The v-sis gene product has been identified in simian sarcoma virus-normal rat kidney-transformed cells as a PDGF-related protein of 28 kDa (5,24), termed p28sis, and PDGF-related proteins of 20 (8) and 17 (23) kDa have been detected in the medium of simian sarcoma virus-normal rabbit kidneytransformed cells. The conditioned media from simian sarcoma virus-transformed cells is able to cause autophosphorylation of the cell surface PDGF receptor, lending support to the autocrine model of transformation (4,8,15,(23)(24)(25).…”

mentioning

confidence: 99%

“…second round of transfection and hybridization. Nucleotide sequencing (24) and restriction mapping were used to confirm the presence of the mutations. These mutations result in the following substitutions: leucine25 to arginine, valine29 to glutamate, and glycine31-glycine32 to aspartate-arginine (Fig.…”

mentioning

confidence: 99%

Biosynthesis of the v-sis gene product: signal sequence cleavage, glycosylation, and proteolytic processing.

Hannink¹,

Donoghue²

1986

Mol. Cell. Biol.

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The v-sis oncogene and its cellular homolog c-sis encode chain B of platelet-derived growth factor. Cells transformed by v-sis produce a platelet-derived growth factor-related molecule which is able to stimulate the platelet-derived growth factor receptor in an autocrine fashion. Site-directed mutagenesis was used to construct several mutations which substitute charged residues for hydrophobic residues in the proposed signal sequence of the v-sis gene product. Two of these mutations resulted in the synthesis of altered v-sis gene products with an unexpected nuclear location and a loss of biological activity. We also report here the intracellular localization of the v-sis gene product to the endoplasmic reticulum-Golgi compartment, where signal sequence cleavage and N-linked glycosylation occur. The v-sis gene product contains no transmembrane regions, as it is completely protected within isolated microsomes from trypsin proteolysis. Site-directed mutagenesis was also used to alter a proposed proteolytic processing site in the v-sis gene product. This mutant v-sis gene, which encodes Asn-Ser in place of Lys-Arg at residues 110 to 111, was found to retain full biological activity.

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Structural and immunological similarities between simian sarcoma virus gene product(s) and human platelet-derived growth factor

Cited by 328 publications

References 24 publications

Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases

Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases

Structural and functional aspects of platelet-derived growth factor

Biosynthesis of the v-sis gene product: signal sequence cleavage, glycosylation, and proteolytic processing.

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