Effects of FK506-binding protein 12 and FK506 on autophosphorylation of epidermal growth factor receptor.
FK506-binding proteins and cyclophilins are intracellular proteins that express peptidylproline cis-trans-isomerase (PPIase) activity. The effects of FK506-binding protein 12 (FKBP12) and the cyclophilins 18 and 23 on autophosphorylation of the epidermal growth factor (EGF) receptor prepared from plasma membranes of the human epidermoid cell line A431 have been investigated. Whereas FKBP12 inhibited EGF receptor tyrosine kinase activity in a concentration-dependent manner, the cyclophilins did not affect autophosphorylation. In contrast to the wild-type enzyme, several variants of FKBP12 with greatly reduced PPIase activity were unable to suppress EGF receptor tyrosine kinase significantly. Pervanadate an inhibitor of protein tyrosine phosphatases, abolished the effect of FKBP12 on EGF receptor autophosphorylation. Finally, FK506 and rapamycin, which are known to block the PPIase activity of FKBP12, induced a significant stimulation of EGF receptor autophosphorylation in intact A431 cells suggesting suppression of EGF receptor autophosphorylation by intracellular FKBP12 in vivo. Taken together the data point to an inhibitory function of FKBP12 in EGF receptor signaling, possibly induced by stimulation of a protein tyrosine phosphatase coupled to the EGF receptor. Both PPIase activity and substrate specificity of FKBP12 seem to be indispensable for this effect.
Lopez-Ilasaca
M
M
Research Unit, Molecular Cell Biology, Drackendorfer Strabetae 1, D-07747 Jena, Germany.
Schiene
C
C
Küllertz
G
G
Tradler
T
T
Fischer
G
G
Wetzker
R
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D002294:Carcinoma, Squamous Cell; D002352:Carrier Proteins / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D014644:Genetic Variation; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D011994:Recombinant Proteins; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D066246:ErbB Receptors; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus