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.

Subverted signalling by protein kinase CK2 in Delta F508 CFTR expressing cells / Venerando, Andrea; Pagano, MARIO ANGELO PRIMO; Cozza, Giorgio; Arrigoni, Giorgio; Metha, A; Pinna, Lorenzo. - In: THE FEBS JOURNAL. - ISSN 1742-464X. - 278:Supplement S1(2011), pp. 387-387. [10.1111/j.1742-4658.2011.08137.x]

Subverted signalling by protein kinase CK2 in Delta F508 CFTR expressing cells

VENERANDO, ANDREA;
2011

Abstract

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.
Subverted signalling by protein kinase CK2 in Delta F508 CFTR expressing cells / Venerando, Andrea; Pagano, MARIO ANGELO PRIMO; Cozza, Giorgio; Arrigoni, Giorgio; Metha, A; Pinna, Lorenzo. - In: THE FEBS JOURNAL. - ISSN 1742-464X. - 278:Supplement S1(2011), pp. 387-387. [10.1111/j.1742-4658.2011.08137.x]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2915875
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