Growth factor control of epidermal growth factor receptor kinase activity via an intramolecular mechanism.
The mechanism by which the protein kinase activity of the epidermal growth factor (EGF) receptor is activated by binding of growth factor was investigated. Detergent-solubilized receptor in monomeric form was isolated by sucrose density gradient centrifugation and both its kinase and autophosphorylation activities monitored. In a low ionic strength medium and with MnCl2 as an activator, the activity of the monomeric receptor was EGF-independent. However, with 0.25 M ammonium sulfate present, the MnCl2-stimulated kinase activity was strikingly EGF-dependent. In contrast, the kinase activity expressed in the presence of MgCl2 showed growth factor control in the absence of added salt. Under the conditions of these experiments there was apparently little tendency for growth factor to induce aggregation of the receptor, indicating that the allosteric activation of the receptor kinase by EGF occurred via an intramolecular mechanism. Whereas detergent-solubilized receptor was the subject of these studies, the kinase activity of cell surface receptors might also be controlled by an intramolecular mechanism. These results indicate that an individual receptor molecule has the potential to function as a transmembrane signal transducer.
Koland
J G
JG
Department of Pharmacology, New York State College of Veterinary Medicine, Cornell University, Ithaca 14853.
Cerione
R A
RA
D000645:Ammonium Sulfate / Q000494:pharmacology; D002712:Chlorides; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008274:Magnesium / Q000494:pharmacology; D015636:Magnesium Chloride; D008345:Manganese / Q000494:pharmacology; D017895:Manganese Compounds; D017830:Octoxynol; D011092:Polyethylene Glycols; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*
D002712:Chlorides; D017895:Manganese Compounds; D015636:Magnesium Chloride; D011092:Polyethylene Glycols; D008345:Manganese; D004815:Epidermal Growth Factor; D017830:Octoxynol; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D008274:Magnesium; C025340:manganese chloride; D000645:Ammonium Sulfate