Faculty Research 1990 - 1999


EGF receptor down-regulation attenuates ligand-induced second messenger formation.

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Calcium: me, Cell-Line, Chromatography-High-Pressure-Liquid, Cytosol: de, me, Down-Regulation-(Physiology), Epidermal-Growth-Factor-Urogastrone, Flow-Cytometry, Hepatoma, Human, Inositol-Phosphates: me, Ligands, Liver-Neoplasms, Molecular-Weight, Receptors-Epidermal-Growth-Factor-Urogastrone, Second-Messenger-Systems, SUPPORT-U-S-GOVT-P-H-S

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Exp Cell Res 1990 Mar;187(1):134-42


DK35914/DK/NIDDK, DK19525/DK/NIDDK, CA37225/CA/NCI


Epidermal growth factor (EGF)-induced increases in cytosolic Ca2+ and inositol polyphosphate production were compared in a human hepatocellular carcinoma-derived cell line, PLC/PRF/5, and in an EGF receptor-overexpressing subline, NPLC/PRF/5. Formation of these second messengers was correlated to EGF receptor display at the cell surface by monitoring ligand-induced EGF receptor down-regulation. Both cell lines exhibited a strikingly similar cytosolic Ca2+ increase upon exposure to EGF. The initial inositol phosphate responses were also similar in the two cell lines; inositol 1,4,5-trisphosphate increased within 10-15 s and returned to prestimulatory values after 2 min in both cell lines, while inositol tetrakisphosphate and inositol 1,3,4-trisphosphate were elevated after a 2-min exposure to EGF. At later times the responses were markedly different; NPLC/PRF/5 cells exhibited prolonged production of inositol 1,3,4-trisphosphate and inositol tetrakisphosphate (maximum at 1-3 h) but PLC/PRF/5 cells showed decreased levels of these isomers after 10 min and a return to basal values by 1 h. Exposure of PLC/PRF/5 cells to EGF caused a progressive decrease in the amount of EGF receptor at the cell surface whereas such treatment did not change the surface receptor levels in NPLC/PRF/5 cells. Kinetic analysis of EGF receptor down-regulation showed that receptor internalization was rapid enough to account for the transient nature of the inositol phosphate response in PLC/PRF/5 cells. Thus, the divergent patterns of signaling exhibited by the two cell lines may reflect differences in the efficiency of EGF-induced down-regulation of surface receptors.

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