Rapid turnover of the platelet-derived growth factor receptor in sis-transformed cells and reversal by suramin. Implications for the mechanism of autocrine transformation.
In cells transformed by either v-sis or c-sis, the majority of the newly synthesized platelet-derived growth factor (PDGF) receptors fail to reach the cell surface and are rapidly degraded. This rapid turnover (t1/2 less than 30 min) appears to result from interaction of the sis gene product with the PDGF receptor in the endoplasmic reticulum and/or Golgi apparatus during their intracellular routing from the endoplasmic reticulum to the plasma membrane or extracellular compartment. Several lines of evidence support this hypothesis. 1) Both the 160-kDa precursor and the intracellular 180-kDa mature form of the PDGF receptor possessed ligand binding activity for PDGF; 2) both the 160-kDa precursor and the 180-kDa mature form of the receptor in sis-transformed cells were found to be activated (phosphorylated); 3) protamine, a competitive inhibitor for PDGF or v-sis gene product binding to the cell-surface receptor, did not affect the rapid turnover of the PDGF receptor in sis-transformed cells; 4) suramin, an inhibitor for PDGF or v-sis gene product binding to the PDGF receptor, not only reversed the rapid turnover of the PDGF receptor in sis-transformed cells, but also increased the secretion of sis gene products; and 5) rapid turnover of the PDGF receptor was only observed in sis-transformed cells but not in cells transformed by other oncogenes. We suggest that the persistence of a mitogenic signal from cellular organelles, arising from the intracellular interaction of sis gene products with newly synthesized PDGF receptors, is the mechanism for autocrine transformation by sis.
Huang
S S
SS
E.A. Doisy Department of Biochemistry, St. Louis University School of Medicine, Missouri 63104.
Huang
J S
JS
D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D006596:Hexosaminidases / Q000378:metabolism; D006801:Humans; D007163:Immunosorbent Techniques; D008970:Molecular Weight; D020575:Oncogene Proteins v-sis; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011498:Protein Precursors / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor; D012190:Retroviridae / Q000502:physiology*; D012191:Retroviridae Proteins / Q000378:metabolism / Q000494:pharmacology*; D012842:Sarcoma Virus, Woolly Monkey / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology*
D020575:Oncogene Proteins v-sis; D010982:Platelet-Derived Growth Factor; D011498:Protein Precursors; D011956:Receptors, Cell Surface; D012191:Retroviridae Proteins; D013498:Suramin; D017479:Receptors, Platelet-Derived Growth Factor; D006596:Hexosaminidases