C. Kuhne et al., Differential regulation of human papillomavirus E6 by protein kinase A: conditional degradation of human discs large protein by oncogenic E6, ONCOGENE, 19(51), 2000, pp. 5884-5891
The protein Kinase A (PKA) pathway was found to selectively regulate the fu
nction of oncogenic but not non-oncogenic E6 proteins, High risk E6 protein
s are phosphorylated at their D1g/PDZ binding motif at the C-terminus by a
PKA like activity. This PKA and PDZ binding module is found only for human
PV, is strictly conserved in all the transforming HPVs and is absent in all
the low risk HPV types. We present evidence of a conditional regulation of
E6 induced degradation of Dig, HPV18E6 positive but not HPV negative kerat
inocytes exhibit increased Dig steady state levels under conditions of high
PKA activity, with a concomitant increase in the presence of Dig at tight
junctions, vitro binding experiments show that E6 phosphorylation by PKA re
duces its binding to Dig and molecular modelling can explain this observati
on in a structural context, E6 dependent degradation of Dig in cells with h
igh PKA levels is inhibited and this is dependent on phosphorylation of the
PDZ binding site in E6, In contrast, the degradation of p53 induced by E6
is not affected by PKA, We propose a differential regulation of E6 for the
ubiquitin mediated degradation of specific E6 target proteins.