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Reciprocal Protein Kinase A Regulatory Interactions between Cystic Fibrosis Transmembrane Conductance Regulator and Na+/H+ Exchanger Isoform 3 in a Renal Polarized Epithelial Cell Model
Although Cystic fibrosis transmembrane conductance regulator (CFTR) has been shown to regulate the activity of NHE3, the potential reciprocal interaction of NHE3 to modulate the protein kinase A (PKA)-dependent regulation of CFTR in epithelial cells is still unknown. In the present work, we describe...
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| Published in: | The Journal of biological chemistry 2002-06, Vol.277 (24), p.21480-21488 |
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| Main Authors: | , , , , , , , , , |
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| container_end_page | 21488 |
| container_issue | 24 |
| container_start_page | 21480 |
| container_title | The Journal of biological chemistry |
| container_volume | 277 |
| creator | Bagorda, Anna Guerra, Lorenzo Di Sole, Francesca Hemle-Kolb, Corinna Cardone, Rosa A Fanelli, Teresa Reshkin, Stephan J Gisler, Serge M Murer, Heini Casavola, Valeria |
| description | Although Cystic fibrosis transmembrane conductance regulator (CFTR) has been shown to regulate the activity of NHE3, the potential
reciprocal interaction of NHE3 to modulate the protein kinase A (PKA)-dependent regulation of CFTR in epithelial cells is
still unknown. In the present work, we describe experiments to define the interactions between CFTR and NHE3 with the regulatory,
scaffolding protein, NHERF that organize their PKA-dependent regulation in a renal epithelial cell line that expresses endogenous
CFTR. The expression of rat NHE3 significantly decreased PKA-dependent activation of CFTR without altering CFTR expression,
and this decrease was prevented by mutation of either of the two rat NHE3 PKA target serines to alanine (S552A or S605A).
Inhibition of CFTR expression by antisense treatment resulted in an acute decrease in PKA-dependent regulation of NHE3 activity.
CFTR, NHE3, and ezrin were recognized by NHERF-2 but not NHERF-1 in glutathione S -transferase pull-down experiments. Ezrin may function as a protein kinase A anchoring protein (AKAP) in this signaling complex,
because blocking the binding of PKA to an AKAP by incubation with the S-Ht31 peptide inhibited the PKA-dependent regulation
of CFTR in the absence of NHE3. In the A6-NHE3 cells S-Ht31 blocked the PKA regulation of NHE3 whereas it now failed to affect
the regulation of CFTR. We conclude that CFTR and NHE3 reciprocally interact via a shared regulatory complex comprised of
NHERF-2, ezrin, and PKA. |
| doi_str_mv | 10.1074/jbc.M112245200 |
| format | article |
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reciprocal interaction of NHE3 to modulate the protein kinase A (PKA)-dependent regulation of CFTR in epithelial cells is
still unknown. In the present work, we describe experiments to define the interactions between CFTR and NHE3 with the regulatory,
scaffolding protein, NHERF that organize their PKA-dependent regulation in a renal epithelial cell line that expresses endogenous
CFTR. The expression of rat NHE3 significantly decreased PKA-dependent activation of CFTR without altering CFTR expression,
and this decrease was prevented by mutation of either of the two rat NHE3 PKA target serines to alanine (S552A or S605A).
Inhibition of CFTR expression by antisense treatment resulted in an acute decrease in PKA-dependent regulation of NHE3 activity.
CFTR, NHE3, and ezrin were recognized by NHERF-2 but not NHERF-1 in glutathione S -transferase pull-down experiments. Ezrin may function as a protein kinase A anchoring protein (AKAP) in this signaling complex,
because blocking the binding of PKA to an AKAP by incubation with the S-Ht31 peptide inhibited the PKA-dependent regulation
of CFTR in the absence of NHE3. In the A6-NHE3 cells S-Ht31 blocked the PKA regulation of NHE3 whereas it now failed to affect
the regulation of CFTR. We conclude that CFTR and NHE3 reciprocally interact via a shared regulatory complex comprised of
NHERF-2, ezrin, and PKA.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M112245200</identifier><identifier>PMID: 11937500</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Animals ; Biotinylation ; Blotting, Western ; Cell Line ; Chlorine - metabolism ; Cyclic AMP - metabolism ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism ; Cytoplasm - metabolism ; Cytoskeletal Proteins ; Dose-Response Relationship, Drug ; Epithelial Cells - metabolism ; Glutathione Transferase - metabolism ; Hydrogen-Ion Concentration ; Ions ; Microscopy, Fluorescence ; Mutation ; Oligonucleotides, Antisense - pharmacology ; Peptides - chemistry ; Phosphoproteins - metabolism ; Phosphorylation ; Protein Binding ; Protein Isoforms ; Rats ; Recombinant Fusion Proteins - metabolism ; Sodium-Hydrogen Exchangers - metabolism ; Time Factors ; Transfection</subject><ispartof>The Journal of biological chemistry, 2002-06, Vol.277 (24), p.21480-21488</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c426t-95cdfd1e62d972d5292463c586b0478f8d32b88d1732ba36e2f0cc825d3829173</citedby><cites>FETCH-LOGICAL-c426t-95cdfd1e62d972d5292463c586b0478f8d32b88d1732ba36e2f0cc825d3829173</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11937500$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bagorda, Anna</creatorcontrib><creatorcontrib>Guerra, Lorenzo</creatorcontrib><creatorcontrib>Di Sole, Francesca</creatorcontrib><creatorcontrib>Hemle-Kolb, Corinna</creatorcontrib><creatorcontrib>Cardone, Rosa A</creatorcontrib><creatorcontrib>Fanelli, Teresa</creatorcontrib><creatorcontrib>Reshkin, Stephan J</creatorcontrib><creatorcontrib>Gisler, Serge M</creatorcontrib><creatorcontrib>Murer, Heini</creatorcontrib><creatorcontrib>Casavola, Valeria</creatorcontrib><title>Reciprocal Protein Kinase A Regulatory Interactions between Cystic Fibrosis Transmembrane Conductance Regulator and Na+/H+ Exchanger Isoform 3 in a Renal Polarized Epithelial Cell Model</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Although Cystic fibrosis transmembrane conductance regulator (CFTR) has been shown to regulate the activity of NHE3, the potential
reciprocal interaction of NHE3 to modulate the protein kinase A (PKA)-dependent regulation of CFTR in epithelial cells is
still unknown. In the present work, we describe experiments to define the interactions between CFTR and NHE3 with the regulatory,
scaffolding protein, NHERF that organize their PKA-dependent regulation in a renal epithelial cell line that expresses endogenous
CFTR. The expression of rat NHE3 significantly decreased PKA-dependent activation of CFTR without altering CFTR expression,
and this decrease was prevented by mutation of either of the two rat NHE3 PKA target serines to alanine (S552A or S605A).
Inhibition of CFTR expression by antisense treatment resulted in an acute decrease in PKA-dependent regulation of NHE3 activity.
CFTR, NHE3, and ezrin were recognized by NHERF-2 but not NHERF-1 in glutathione S -transferase pull-down experiments. Ezrin may function as a protein kinase A anchoring protein (AKAP) in this signaling complex,
because blocking the binding of PKA to an AKAP by incubation with the S-Ht31 peptide inhibited the PKA-dependent regulation
of CFTR in the absence of NHE3. In the A6-NHE3 cells S-Ht31 blocked the PKA regulation of NHE3 whereas it now failed to affect
the regulation of CFTR. We conclude that CFTR and NHE3 reciprocally interact via a shared regulatory complex comprised of
NHERF-2, ezrin, and PKA.</description><subject>Animals</subject><subject>Biotinylation</subject><subject>Blotting, Western</subject><subject>Cell Line</subject><subject>Chlorine - metabolism</subject><subject>Cyclic AMP - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Cystic Fibrosis Transmembrane Conductance Regulator - metabolism</subject><subject>Cytoplasm - metabolism</subject><subject>Cytoskeletal Proteins</subject><subject>Dose-Response Relationship, Drug</subject><subject>Epithelial Cells - metabolism</subject><subject>Glutathione Transferase - metabolism</subject><subject>Hydrogen-Ion Concentration</subject><subject>Ions</subject><subject>Microscopy, Fluorescence</subject><subject>Mutation</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>Peptides - chemistry</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Protein Isoforms</subject><subject>Rats</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Sodium-Hydrogen Exchangers - metabolism</subject><subject>Time Factors</subject><subject>Transfection</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNpFUctqGzEUFaWlcdNsuyxadBfG0WMemmUYnMY0aUJIITuhke54FGYkI8kk7p_176rggO_mwOWccx8HoW-ULClpyovnXi9vKWWsrBghH9CCEsELXtGnj2hBCKNFyypxgr7E-ExylS39jE4obXlTEbJA_x5A223wWk34PvgE1uFf1qkI-BI_wGY3qeTDHq9dgqB0st5F3EN6AXC428dkNb6yffDRRvwYlIszzH1GwJ13ZqeTchqOTlg5g3-r84vrc7x61aNyGwh4Hf3gw4w5zuNVZru3dfykgv0LBq-2No0w2dzsYJrwrTcwfUWfBjVFOHvHU_TnavXYXRc3dz_X3eVNoUtWp6KttBkMhZqZtmGmYi0ra64rUfekbMQgDGe9EIY2GRWvgQ1Ea8EqwwVrc_cULQ--Oh8ZAwxyG-yswl5SIt8ykDkDecwgC74fBNtdP4M50t-fngk_DoTRbsYXG0D21usRZsmaRrJSMloKwv8DTKCQUQ</recordid><startdate>20020614</startdate><enddate>20020614</enddate><creator>Bagorda, Anna</creator><creator>Guerra, Lorenzo</creator><creator>Di Sole, Francesca</creator><creator>Hemle-Kolb, Corinna</creator><creator>Cardone, Rosa A</creator><creator>Fanelli, Teresa</creator><creator>Reshkin, Stephan J</creator><creator>Gisler, Serge M</creator><creator>Murer, Heini</creator><creator>Casavola, Valeria</creator><general>American Society for Biochemistry and Molecular Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20020614</creationdate><title>Reciprocal Protein Kinase A Regulatory Interactions between Cystic Fibrosis Transmembrane Conductance Regulator and Na+/H+ Exchanger Isoform 3 in a Renal Polarized Epithelial Cell Model</title><author>Bagorda, Anna ; Guerra, Lorenzo ; Di Sole, Francesca ; Hemle-Kolb, Corinna ; Cardone, Rosa A ; Fanelli, Teresa ; Reshkin, Stephan J ; Gisler, Serge M ; Murer, Heini ; Casavola, Valeria</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c426t-95cdfd1e62d972d5292463c586b0478f8d32b88d1732ba36e2f0cc825d3829173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Biotinylation</topic><topic>Blotting, Western</topic><topic>Cell Line</topic><topic>Chlorine - metabolism</topic><topic>Cyclic AMP - metabolism</topic><topic>Cyclic AMP-Dependent Protein Kinases - metabolism</topic><topic>Cystic Fibrosis Transmembrane Conductance Regulator - metabolism</topic><topic>Cytoplasm - metabolism</topic><topic>Cytoskeletal Proteins</topic><topic>Dose-Response Relationship, Drug</topic><topic>Epithelial Cells - metabolism</topic><topic>Glutathione Transferase - metabolism</topic><topic>Hydrogen-Ion Concentration</topic><topic>Ions</topic><topic>Microscopy, Fluorescence</topic><topic>Mutation</topic><topic>Oligonucleotides, Antisense - pharmacology</topic><topic>Peptides - chemistry</topic><topic>Phosphoproteins - metabolism</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>Protein Isoforms</topic><topic>Rats</topic><topic>Recombinant Fusion Proteins - metabolism</topic><topic>Sodium-Hydrogen Exchangers - metabolism</topic><topic>Time Factors</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bagorda, Anna</creatorcontrib><creatorcontrib>Guerra, Lorenzo</creatorcontrib><creatorcontrib>Di Sole, Francesca</creatorcontrib><creatorcontrib>Hemle-Kolb, Corinna</creatorcontrib><creatorcontrib>Cardone, Rosa A</creatorcontrib><creatorcontrib>Fanelli, Teresa</creatorcontrib><creatorcontrib>Reshkin, Stephan J</creatorcontrib><creatorcontrib>Gisler, Serge M</creatorcontrib><creatorcontrib>Murer, Heini</creatorcontrib><creatorcontrib>Casavola, Valeria</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bagorda, Anna</au><au>Guerra, Lorenzo</au><au>Di Sole, Francesca</au><au>Hemle-Kolb, Corinna</au><au>Cardone, Rosa A</au><au>Fanelli, Teresa</au><au>Reshkin, Stephan J</au><au>Gisler, Serge M</au><au>Murer, Heini</au><au>Casavola, Valeria</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Reciprocal Protein Kinase A Regulatory Interactions between Cystic Fibrosis Transmembrane Conductance Regulator and Na+/H+ Exchanger Isoform 3 in a Renal Polarized Epithelial Cell Model</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2002-06-14</date><risdate>2002</risdate><volume>277</volume><issue>24</issue><spage>21480</spage><epage>21488</epage><pages>21480-21488</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Although Cystic fibrosis transmembrane conductance regulator (CFTR) has been shown to regulate the activity of NHE3, the potential
reciprocal interaction of NHE3 to modulate the protein kinase A (PKA)-dependent regulation of CFTR in epithelial cells is
still unknown. In the present work, we describe experiments to define the interactions between CFTR and NHE3 with the regulatory,
scaffolding protein, NHERF that organize their PKA-dependent regulation in a renal epithelial cell line that expresses endogenous
CFTR. The expression of rat NHE3 significantly decreased PKA-dependent activation of CFTR without altering CFTR expression,
and this decrease was prevented by mutation of either of the two rat NHE3 PKA target serines to alanine (S552A or S605A).
Inhibition of CFTR expression by antisense treatment resulted in an acute decrease in PKA-dependent regulation of NHE3 activity.
CFTR, NHE3, and ezrin were recognized by NHERF-2 but not NHERF-1 in glutathione S -transferase pull-down experiments. Ezrin may function as a protein kinase A anchoring protein (AKAP) in this signaling complex,
because blocking the binding of PKA to an AKAP by incubation with the S-Ht31 peptide inhibited the PKA-dependent regulation
of CFTR in the absence of NHE3. In the A6-NHE3 cells S-Ht31 blocked the PKA regulation of NHE3 whereas it now failed to affect
the regulation of CFTR. We conclude that CFTR and NHE3 reciprocally interact via a shared regulatory complex comprised of
NHERF-2, ezrin, and PKA.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>11937500</pmid><doi>10.1074/jbc.M112245200</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2002-06, Vol.277 (24), p.21480-21488 |
| issn | 0021-9258 1083-351X |
| language | eng |
| recordid | cdi_crossref_primary_10_1074_jbc_M112245200 |
| source | BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS |
| subjects | Animals Biotinylation Blotting, Western Cell Line Chlorine - metabolism Cyclic AMP - metabolism Cyclic AMP-Dependent Protein Kinases - metabolism Cystic Fibrosis Transmembrane Conductance Regulator - metabolism Cytoplasm - metabolism Cytoskeletal Proteins Dose-Response Relationship, Drug Epithelial Cells - metabolism Glutathione Transferase - metabolism Hydrogen-Ion Concentration Ions Microscopy, Fluorescence Mutation Oligonucleotides, Antisense - pharmacology Peptides - chemistry Phosphoproteins - metabolism Phosphorylation Protein Binding Protein Isoforms Rats Recombinant Fusion Proteins - metabolism Sodium-Hydrogen Exchangers - metabolism Time Factors Transfection |
| title | Reciprocal Protein Kinase A Regulatory Interactions between Cystic Fibrosis Transmembrane Conductance Regulator and Na+/H+ Exchanger Isoform 3 in a Renal Polarized Epithelial Cell Model |
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