The PDZ-interacting Domain of Cystic Fibrosis Transmembrane Conductance Regulator Is Required for Functional Expression in the Apical Plasma Membrane

Moyer, Bryan D.; Duhaime, Marc; Shaw, Collin M.; Denton, Jerod S.; Reynolds, Donna; Karlson, Katherine H.; Pfeiffer, Jason; Wang, Shusheng; Mickle, John E.; Milewski, Michał; Cutting, Garry R.; Guggino, William B.; Li, Min; Stanton, Bruce A.

doi:10.1016/s0021-9258(19)61481-x

Cited by 140 publications

(9 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another means of membrane targeting of proteins is interaction between PDZ domain‐containing proteins and proteins with COOH‐terminal PDZ ligand motifs, which are often integral membrane proteins (Moyer et al, 2000). It is noteworthy that a Class I COOH‐terminal ligand motif is present in PKA catalytic subunit alpha (‐T‐E‐F).…”

Section: Resultsmentioning

confidence: 99%

Phosphoproteomic identification of vasopressin‐regulated protein kinases in collecting duct cells

Datta

Yang

Salhadar

et al. 2021

British J Pharmacology

View full text Add to dashboard Cite

Background and Purpose The peptide hormone vasopressin regulates water transport in the renal collecting duct largely via the V2 receptor, which triggers a cAMP‐mediated activation of a PKA‐dependent signalling network. The protein kinases downstream from PKA have not been fully identified or mapped to regulated phosphoproteins. Experimental Approach We carried out systems‐level analysis of large‐scale phosphoproteomic data quantifying vasopressin‐induced changes in phosphorylation in aquaporin‐2‐expressing cultured collecting duct (mpkCCD) cells. Quantification was done using stable isotope labelling (SILAC method). Key Results Six hundred forty phosphopeptides were quantified. Stringent statistical analysis identified significant changes in response to vasopressin in 429 of these phosphopeptides. The corresponding phosphoproteins were mapped to known vasopressin‐regulated cellular processes. The vasopressin‐regulated sites were classified according to the sequences surrounding the phosphorylated amino acids giving 11 groups. Among the vasopressin‐regulated phosphoproteins were 25 distinct protein kinases. Among these, six plus PKA appeared to account for phosphorylation of about 81% of the 313 vasopressin‐regulated phosphorylation sites. The six downstream kinases were salt‐inducible kinase 2 (Sik2), cyclin‐dependent kinase 18 (Cdk18), calmodulin‐dependent kinase kinase 2 (Camkk2), protein kinase D2 (Prkd2), mitogen‐activated kinase 3 (Mapk3) and myosin light chain kinase (Mylk). Conclusion and Implications In V2 receptor‐mediated signalling, PKA is at the head of a complex network that includes at least six downstream vasopressin‐regulated protein kinases that are prime targets for future study. The extensive phosphoproteomic data reported in this study are provided as a web‐based data resource for future studies of GPCRs.

show abstract

Section: Resultsmentioning

confidence: 99%

Phosphoproteomic identification of vasopressin‐regulated protein kinases in collecting duct cells

Datta

Yang

Salhadar

et al. 2021

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…Notably, though truncation of CFTR at NBD2 results in some retained function, domains at the C terminus are important for stability and gating, and these domains are preserved when exon 23 is skipped (SI Appendix, Fig. S2) (28,29,50,51).…”

Section: Discussionmentioning

confidence: 99%

Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis

Michaels

Peña‐Rasgado

Kotaria

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

CFTR gene mutations that result in the introduction of premature termination codons (PTCs) are common in cystic fibrosis (CF). This mutation type causes a severe form of the disease, likely because of low CFTR messenger RNA (mRNA) expression as a result of nonsense-mediated mRNA decay, as well as the production of a nonfunctional, truncated CFTR protein. Current therapeutics for CF, which target residual protein function, are less effective in patients with these types of mutations due in part to low CFTR protein levels. Splice-switching antisense oligonucleotides (ASOs), designed to induce skipping of exons in order to restore the mRNA open reading frame, have shown therapeutic promise preclinically and clinically for a number of diseases. We hypothesized that ASO-mediated skipping of CFTR exon 23 would recover CFTR activity associated with terminating mutations in the exon, including CFTR p.W1282X, the fifth most common mutation in CF. Here, we show that CFTR lacking the amino acids encoding exon 23 is partially functional and responsive to corrector and modulator drugs currently in clinical use. ASO-induced exon 23 skipping rescued CFTR expression and chloride current in primary human bronchial epithelial cells isolated from a homozygote CFTR-W1282X patient. These results support the use of ASOs in treating CF patients with CFTR class I mutations in exon 23 that result in unstable CFTR mRNA and truncations of the CFTR protein.

show abstract

“…Besides its role as a Cl - channel, CFTR also regulates the activity of various ion channels and transporters, mainly via direct protein-protein interactions [ 18 , 19 ]. Some of these interactions might be mediated by the association of CFTR via its C-terminal PDZ-binding motif (D-T-R-L) with the PDZ-binding domains of other proteins, such as NHERF [ 11 , 12 , 20 , 21 ]. CFTR also functions as regulator of ATP release [ 22 , 23 ], which might be important for EC function because the released ATP could in turn bind to endothelial P2Y2 and P2X4 receptors [for a review, see 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…The two PDZ domain protein NHERF associates also with the actin cytoskeleton via members of the ezrin/radixin/moesin family [ 10 , 11 ]. It is also well established that the C terminus of CFTR constitutes a PDZ-interacting domain (QDTRL for the last five C-terminal amino acids) that is required for CFTR polarization to the apical plasma membrane and interaction with the PDZ domain-containing protein NHERF [ 12 ]. Thus, both TRP4 and CFTR may bind to similar PDZ-domain proteins.…”

Section: Introductionmentioning

confidence: 99%

Functional interaction between TRP4 and CFTR in mouse aorta endothelial cells

et al. 2001

View full text Add to dashboard Cite

show abstract

The PDZ-interacting Domain of Cystic Fibrosis Transmembrane Conductance Regulator Is Required for Functional Expression in the Apical Plasma Membrane

Cited by 140 publications

References 46 publications

Phosphoproteomic identification of vasopressin‐regulated protein kinases in collecting duct cells

Phosphoproteomic identification of vasopressin‐regulated protein kinases in collecting duct cells

Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis

Functional interaction between TRP4 and CFTR in mouse aorta endothelial cells

Contact Info

Product

Resources

About