CFTR: a hub for kinases and crosstalk of cAMP and Ca²⁺

Abstract

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR). The resulting disease is pleiotropic consistent with the idea that CFTR acts as a node within a network of signalling proteins. CFTR is not only a regulator of multiple transport proteins and controlled by numerous kinases but also participates in many signalling pathways that are disrupted after expression of its commonest mutant (F508del‐CFTR). It operates in membrane compartments creating a scaffold for cytoskeletal elements, surface receptors, kinases and phosphodiesterases. CFTR is exposed to membrane‐local second messengers such that a CFTR‐interacting, low cellular energy sensor kinase (AMP‐ and ADP‐activated kinase, AMPK) signals through a high energy phosphohistidine protein kinase (nucleoside diphosphate kinase, NDPK). CFTR also translocates a Ca2+‐dependent adenylate cyclase to its proximity so that a rigid separation between cAMP‐dependent and Ca2+‐dependent regulation of Cl− transport becomes obsolete. In the presence of wild‐type CFTR, parallel activation of CFTR and outwardly rectifying anoctamin 6 Cl− channels is observed, while the Ca2+‐activated anoctamin 1 Cl− channel is inhibited. In contrast, in CF cells, CFTR is missing/mislocalized and the outwardly rectifying chloride channel is attenuated while Ca2+‐dependent Cl− secretion (anoctamin 1) appears upregulated. Additionally, we consider the idea that F508del‐CFTR when trapped in the endoplasmic reticulum augments IP3‐mediated Ca2+ release by providing a shunt pathway for Cl−. CFTR and the IP3 receptor share the characteristic that they both assemble their partner proteins to increase the plasticity of their hub responses. In CF, the CFTR hub fails to form at the plasma membrane, with widespread detrimental consequences for cell signalling.

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

“…In CF cells bearing the common mutant form of CFTR, this PKA/CnA-driven anx 2-S100A10 complex with mutant CFTR fails to form. 80 The recent links between cell calcium and PKA and CFTR function have been reviewed elsewhere by Hanrahan, Kunzelmann and Mehta 20,81 (and cited by Forman-Kay and co-workers 12 ) and will not be discussed further here, but we note that calcineurin coupled to the calcium-binding properties of the annexin family and calmodulin itself now firmly place this regulatory cation with the CFTR family of hub proteins.…”

“…This is consistent with local substrate channeling of the constitutive activity of kinases such as NDPK and CK2 inside a new hub structure located near CFTR that may be shielded from the cytoplasm. Importantly, CK2 is also essential for sodium channel function 20 by phosphorylating two different sites and others suggest that NDPK and CK2 may interact in vitro, but this remains to be confirmed.…”

“…19 In CF, it is established that mutation of CFTR causes a very low residence time and high degradation rate for the mutant (F508-deleted) protein which somehow enhances the function of epithelial sodium channels in a chloride-dependent manner. 20 Later, we identified that chloride-sensitive proteins such as NDPK and annexin A1 are phosphorylated on histidine residues (see summary in Figure 1); for annexin A1 this occurs near the conserved calcium-binding domain of this regulator of inflammation and steroid signaling. 15,17,[21][22][23] Inhibition of NDPK by non-hydrolyzable nucleoside analogs abrogated histidine phosphorylation of annexin A1.…”

Nucleoside diphosphate kinases (NDPKs) in animal development

“…In recent experiments on human bronchial epithelial cells, AMPKalpha1 and NDPK-A (NM23-H1) were found to bind each other, and catalytically active NDPK-A was essential in the transmission of an inhibitory AMPK signal towards an energy consuming process, ion transport [111]. Here, AMPK retards the activity of the cystic fibrosis transmembrane conductance regulator, CFTR, an ion channel whose dysfunction causes cystic fibrosis [112]. This CFTR inhibitory signal requires functional NDPK-A.…”

Abnormal n-6 fatty acid metabolism in cystic fibrosis is caused by activation of AMP-activated protein kinase

“…While the effect of AMPK on PUFA desaturation and elongation is unknown, there is a clear connection between AMPK and CF. AMPK is part of a macromolecular complex that interacts with and regulates CFTR activity ( 24 ). This complex serves as a scaffold that connects CFTR and other ion channels to a number of signal transduction networks.…”