MAST205 competes with cystic fibrosis transmembrane conductance regulator (CFTR)-associated ligand for binding to CFTR to regulate CFTR-mediated fluid transport

Aixia Ren, Weiqiang Zhang, Sunitha Yarlagadda, Chandrima Sinha, Kavisha Arora, Chang Suk Moon, Anjaparavanda P. Naren

Research output: Contribution to journalArticle

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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 upregulated 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 animportant 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.

Original languageEnglish (US)
Pages (from-to)12325-12334
Number of pages10
JournalJournal of Biological Chemistry
Volume288
Issue number17
DOIs
StatePublished - Apr 26 2013

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Cystic Fibrosis Transmembrane Conductance Regulator
Ligands
Fluids
Cell membranes
Processing
Cell Membrane
PDZ Domains
Post-Synaptic Density
Protein-Serine-Threonine Kinases
Herpes Zoster
Molecular mass

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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MAST205 competes with cystic fibrosis transmembrane conductance regulator (CFTR)-associated ligand for binding to CFTR to regulate CFTR-mediated fluid transport. / Ren, Aixia; Zhang, Weiqiang; Yarlagadda, Sunitha; Sinha, Chandrima; Arora, Kavisha; Moon, Chang Suk; Naren, Anjaparavanda P.

In: Journal of Biological Chemistry, Vol. 288, No. 17, 26.04.2013, p. 12325-12334.

Research output: Contribution to journalArticle

Ren, Aixia ; Zhang, Weiqiang ; Yarlagadda, Sunitha ; Sinha, Chandrima ; Arora, Kavisha ; Moon, Chang Suk ; Naren, Anjaparavanda P. / MAST205 competes with cystic fibrosis transmembrane conductance regulator (CFTR)-associated ligand for binding to CFTR to regulate CFTR-mediated fluid transport. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 17. pp. 12325-12334.
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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 upregulated 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 animportant 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.",
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