Cystic fibrosis transmembrane regulator fragments with the Phe508 deletion exert a dual allosteric control over the master kinase CK2

Abstract

Cystic fibrosis mostly follows a single Phe508 deletion in CFTR (cystic fibrosis transmembrane regulator) (CFTRDeltaF508), thereby causing premature fragmentation of the nascent protein with concomitant alterations of diverse cellular functions. We show that CK2, the most pleiotropic protein kinase, undergoes allosteric control of its different cellular forms in the presence of short CFTR peptides encompassing the Phe508 deletion: these CFTRDeltaF508 peptides drastically inhibit the isolated catalytic subunit (alpha) of the kinase and yet up-regulate the holoenzyme, composed of two catalytic and two non-catalytic (beta) subunits. Remarkable agreement between in silico docking and our biochemical data point to different sites for the CFTRDeltaF508 peptide binding on isolated CK2alpha and on CK2beta assembled into the holoenzyme, suggesting that CK2 targeting may be perturbed in cells expressing CFTRDeltaF508; this could shed light on some pleiotropic aspects of cystic fibrosis disease.

Contribution of Casein Kinase 2 and Spleen Tyrosine Kinase to CFTR Trafficking and Protein Kinase A-Induced Activity

“…These data are consistent with a model where the CFTR F508del peptide could bind different sites on isolated CK2alpha subunits than on the CK2(alpha/beta) 2 homodimer and suggest that CK2 targeting to subsets of its many targets may be perturbed in cells expressing F508del CFTR (27).…”

“…Recent results point to a role for F508, S511, and nearby amino acids such as V510 in the allosteric control of the major structural forms of CK2 found in cells (27). These data are consistent with a model where the CFTR F508del peptide could bind different sites on isolated CK2alpha subunits than on the CK2(alpha/beta) 2 homodimer and suggest that CK2 targeting to subsets of its many targets may be perturbed in cells expressing F508del CFTR (27).…”

“…Previous observations evidenced that CK2 was able only to phosphorylate CFTR peptides corresponding to the sequence PGTIKENIIFGVSY 512 D EYRYR, provided that residue Y512 was replaced with phosphotyrosine (26), strongly suggesting the potential for hierarchical phosphorylation, i.e., an interaction between CK2 and SYK at S511, the CK2 consensus, depending on a negative charge at the adjacent tyrosine (26,27).…”

Casein Kinase 2α Regulates Multidrug Resistance-Associated Protein 1 Function via Phosphorylation of Thr249

“…(Yamane and Kinsella, 2005;Di Maira et al, 2007;Mishra et al, 2007;Kramerov et al, 2008;Ruzzene and Pinna, 2010). Elevation of CK2 protein expression in cancer has been associated with tumor aggressiveness and poor prognosis and thus became an attractive target for cancer therapy (Duncan and Litchfield, 2008;Pagano et al, 2010;Trembley et al, 2010).…”

NM23 proteins: innocent bystanders or local energy boosters for CFTR?

“…We need to speak in a common language if those working on CFTR, membrane blocks in autophagy, endosome recycling, and apical membrane function are ever to meet in a common research arena with those interested in phosphohistidine generation. For example, we suggest that new research might aim to link up the following ideas: (a) CK2 is log-orders overactive in CF cells bearing the common CFTR mutation; 93 (b) CK2 phosphorylates key residues on calmodulin located between two of its EF hands; 94 (c) NDPK controls dynamin as the terminal step in endocytosis and is important in cell homing during embryogenesis; 95,96 (d) AMPK and NDPK control adjacent supply points for the cytosolic availability of acetyl units needed for new membrane synthesis; 97 (e) CK2 phosphorylation controls both the localization and function of sodium channels that become dysfunctional after CFTR mutation. [98][99][100] These are some of the known unknowns in CFTR and NDPK research that our model seeks to clarify.…”