Cystic Fibrosis (CF) is almost invariably caused by mutations
occurring in the Cystic Fibrosis Transmembrane Regulator
(CFTR), a protein involved in chloride transport across the cell
membrane. The commonest mutation (accounting for 70% or
more of all CF cases) is the deletion of phenylalanine 508
(DF508) in the nucleotide binding domain-1 (NBD1) of CFTR,
which leads to premature degradation of the nascent protein with
consequent alterations of diverse cellular functions. We recently
showed that protein kinase CK2, which unlike the other protein
kinases has no recognised factors controlling its activity, is susceptible
to allosteric modulation in vitro by peptides reproducing
the sequence encompassing the F508 deletion of CFTR. Consequently
the targeting of several substrates by CK2 is deeply
altered by these DF peptides [1,2]. This prompted us to hypothesize
that in DF508 CFTR expressing cells signalling by CK2
might be subverted, rendering CK2 a new target for therapies
aimed at treating CF.
Lysates of cell lines expressing either wild type or DF508 CFTR
incubated with 32P-GTP in the presence or absence of selective
CK2 inhibitors exhibit significant alterations in the phosphorylation
of CK2 protein substrates. By MS analysis, a number of
proteins whose phosphorylation by CK2 is altered in DF508 cells,
have been identified and some of these have been recognized as
implicated in the process of maturation, stabilization and degradation
of CFTR. Treatment of cells with selective CK2 inhibitors
affects the protein level of CFTR, both wild type and DF508, disclosing
the possibility that modulation of CK2-dependent phosphorylation
may represent a tool for the regulation of expression
and maturation of CFTR, especially in a DF508 CFTR background.
References:
1. Pagano M. A. et al. Biochemistry 2008; 47, 7925–7936.
2. Pagano M. A. et al. Biochem J 2010; 426, 19–29.
