Regulatory Crosstalk by Protein Kinases on CFTR Trafficking and Activity

Abstract

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a member of the ATP binding cassette (ABC) transporter superfamily that functions as a cAMP-activated chloride ion channel in fluid-transporting epithelia. There is abundant evidence that CFTR activity (i.e., channel opening and closing) is regulated by protein kinases and phosphatases via phosphorylation and dephosphorylation. Here, we review recent evidence for the role of protein kinases in regulation of CFTR delivery to and retention in the plasma membrane. We review this information in a broader context of regulation of other transporters by protein kinases because the overall functional output of transporters involves the integrated control of both their number at the plasma membrane and their specific activity. While many details of the regulation of intracellular distribution of CFTR and other transporters remain to be elucidated, we hope that this review will motivate research providing new insights into how protein kinases control membrane transport to impact health and disease.

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

“…36 PKA phosphorylation sites are highly conserved among species, and the R region has been shown to contain the majority of those sites. 36,37 This region may be likened to a net or web structure that is highly plastic with subregions of disorder and coil where transitions occur between these states when targeted by PKA and other protein kinases. One idea is that a randomly fluctuating R region becomes locally ordered with coil structures after regulation to permit the binding of other proteins to assemble a hub (or hubs).…”

Spleen Tyrosine Kinase as a Target Therapy for <b><i>Pseudomonas aeruginosa</i></b> Infection

“…This role of SYK in regulating protein trafficking has been reported previously for other substrates, e.g., trafficking a resident of the trans-Golgi network (TGN) 38 [68], the engaged highaffinity IgE receptor (FcεRI) [69], and the small GTPase Rac1 [70] (shown to play a role in CFTR trafficking and membrane anchoring [71]). Recent findings have shown that phosphorylation of CFTR by SYK results in reducing the abundance of CFTR in the plasma membrane [72]. Importantly, SYK-associated CFTR phosphorylation might not be a major determinant in CF patients.…”

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

“…1 The latter is regulated by the protein trafficking machinery, which controls the process through which a membrane protein is delivered from its place of synthesis -the membrane of the endoplasmic reticulum -to its final destination -the plasma membrane (PM). Besides these anterograde trafficking pathways, channels and transporters also undergo endocytosis followed by either recycling to the PM or targeting to the lysosomal compartment.…”

“…These late trafficking events are controlled by several protein partners, that include protein kinases, myosins and small GTPases, among which Rab proteins. 1 Rab GTPases form the biggest subfamily of the Ras superfamily of small GTPases. As most members of this superfamily, they function as molecular switches alternating between 2 conformational status -a GTP-bound active form and a GDP-bound inactive form.…”

“…2), Rme-1 and myosins as well as some protein kinases. 1 The first report assessing the role of Rab GTPases in CFTR PM trafficking was done using external epitopetagged CFTR constructs and aimed at dissecting possible differences between wt-and F508del-CFTR when expressed in BHK cells. 13 Besides identifying a stability defect for mutant CFTR when rescued to the PM by low temperature incubation, this study identified a role for different Rab proteins in CFTR endocytosis/recycling in BHK cells.…”