Lopez-Ilasaca M, Schiene C, Küllertz G, Tradler T, Fischer G, Wetzker R
Research Unit, Molecular Cell Biology, Drackendorfer Strabetae 1, D-07747 Jena, Germany.
J Biol Chem. 1998 Apr 17;273(16):9430-4. doi: 10.1074/jbc.273.16.9430.
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.
FK506结合蛋白和亲环蛋白是具有肽基脯氨酸顺反异构酶（PPIase）活性的细胞内蛋白。研究了FK506结合蛋白12（FKBP12）和亲环蛋白18及23对从人表皮样细胞系A431的质膜制备的表皮生长因子（EGF）受体自磷酸化的影响。虽然FKBP12以浓度依赖性方式抑制EGF受体酪氨酸激酶活性，但亲环蛋白不影响自磷酸化。与野生型酶相反，几种PPIase活性大大降低的FKBP12变体不能显著抑制EGF受体酪氨酸激酶。钒酸钠是一种蛋白酪氨酸磷酸酶抑制剂，它消除了FKBP12对EGF受体自磷酸化的影响。最后，已知能阻断FKBP12的PPIase活性的FK506和雷帕霉素在完整的A431细胞中诱导了EGF受体自磷酸化的显著刺激，这表明在体内细胞内的FKBP12抑制了EGF受体自磷酸化。综上所述，这些数据表明FKBP12在EGF受体信号传导中具有抑制功能，可能是由与EGF受体偶联的蛋白酪氨酸磷酸酶的刺激所诱导。FKBP12的PPIase活性和底物特异性似乎对此效应都是必不可少的。
