Reduction of epidermal growth factor receptor affinity by heterologous ligands: evidence for a mechanism involving the breakdown of phosphoinositides and the activation of protein kinase C |
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Authors: | K D Brown J Blay R F Irvine J P Heslop M J Berridge |
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Institution: | 2. A.F.R.C. Unit of Insect Neurophysiology and Pharmacology, Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, U.K. |
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Abstract: | The tetradecapeptide bombesin converts epidermal growth factor (EGF) receptors on Swiss 3T3 cells from a high affinity state (KD = 9.8 X 10(-11)M) to a lower affinity state (KD = 1.8 X 10(-9)M). This conversion occurs when the cells are incubated with bombesin at 37 degrees C but not when incubated at 4 degrees C. Previously, a number of other (chemically unrelated) cell growth-promoting peptides and polypeptides have been shown to induce a similar indirect, temperature-dependent reduction of EGF receptor affinity. We have now demonstrated that hormones and growth factors which cross-regulate EGF receptor affinity in Swiss 3T3 cells have a common ability to stimulate the breakdown of phosphoinositides in these cells. We propose that the reduction of EGF receptor affinity is a consequence of the activation of protein kinase C by the diacylglycerol generated by this breakdown. In support of this proposal we have found that exogenously added diacylglycerol reduces the affinity of the Swiss 3T3 cell EGF receptor. |
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Keywords: | EGF epidermal growth factor inositol 1 4 5-trisphosphate inositol 1 4-bisphosphate inositol 1-phosphate PDGF platelet-derived growth factor phosphatidylinositol 4 5-bisphosphate protein kinase C TPA 12-O-tetradecanoyl-phorbol-13-acetate |
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