title: MAST205 competes with cystic fibrosis transmembrane conductance regulator (CFTR)-associated ligand for binding to CFTR to regulate CFTR-mediated fluid transport.
abstract: The PDZ (postsynaptic density-95/discs large/zona occludens-1) domain-based interactions play important roles in regulating the expression and function of the cystic fibrosis transmembrane conductance regulator (CFTR). Several PDZ domain-containing proteins (PDZ proteins for short) have been identified as directly or indirectly interacting with the C terminus of CFTR. To better understand the regulation of CFTR processing, we conducted a genetic screen and identified MAST205 (a microtubule-associated serine/threonine kinase with a molecular mass of 205 kDa) as a new CFTR regulator. We found that overexpression of MAST205 increased the expression of CFTR and augmented CFTR-mediated fluid transport in a dose-dependent manner. Conversely, knockdown of MAST205 inhibited CFTR function. The PDZ motif of CFTR is required for the regulatory role of MAST205 in CFTR expression and function. We further demonstrated that MAST205 and the CFTR-associated ligand competed for binding to CFTR, which facilitated the processing of CFTR and consequently up-regulated the expression and function of CFTR at the plasma membrane. More importantly, we found that MAST205 could facilitate the processing of F508del-CFTR mutant and augment its quantity and channel function at the plasma membrane. Taken together, our data suggest that MAST205 plays an important role in regulating CFTR expression and function. Our findings have important clinical implications for treating CFTR-associated diseases such as cystic fibrosis and secretory diarrheas.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Aixia
authors.initials: A
authors.lastname: Ren
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhang
authors.forename: Sunitha
authors.initials: S
authors.lastname: Yarlagadda
authors.forename: Chandrima
authors.initials: C
authors.lastname: Sinha
authors.forename: Kavisha
authors.initials: K
authors.lastname: Arora
authors.forename: Chang-Suk
authors.initials: CS
authors.lastname: Moon
authors.forename: Anjaparavanda P
authors.initials: AP
authors.lastname: Naren
mesh_terms: D000595:Amino Acid Sequence; D001693:Biological Transport, Active / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D003967:Diarrhea / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D014882:Water-Electrolyte Balance
chemical_list: C505032:CFTR protein, human; D008869:Microtubule-Associated Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C503880:MAST2 protein, human; D017346:Protein Serine-Threonine Kinases