The KSR2-calcineurin complex regulates STIM1-ORAI1 dynamics and store-operated calcium entry (SOCE)
Store-operated calcium entry (SOCE) is the predominant Ca(2+) entry mechanism in nonexcitable cells and controls a variety of physiological and pathological processes. Although significant progress has been made in identifying the components required for SOCE, the molecular mechanisms underlying it...
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| Veröffentlicht in: | Molecular biology of the cell 2014-06, Vol.25 (11), p.1769-1781 |
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| creator | Giurisato, E Gamberucci, A Ulivieri, C Marruganti, S Rossi, E Giacomello, E Randazzo, D Sorrentino, V |
| description | Store-operated calcium entry (SOCE) is the predominant Ca(2+) entry mechanism in nonexcitable cells and controls a variety of physiological and pathological processes. Although significant progress has been made in identifying the components required for SOCE, the molecular mechanisms underlying it are elusive. The present study provides evidence for a direct involvement of kinase suppressor of Ras 2 (KSR2) in SOCE. Using lymphocytes and fibroblasts from ksr2(-/-) mice and shKSR2-depleted cells, we find that KSR2 is critical for the elevation of cytosolic Ca(2+) concentration. Specifically, our results show that although it is dispensable for Ca(2+)-store depletion, KSR2 is required for optimal calcium entry. We observe that KSR2 deficiency affects stromal interaction molecule 1 (STIM1)/ORAI1 puncta formation, which is correlated with cytoskeleton disorganization. Of interest, we find that KSR2-associated calcineurin is crucial for SOCE. Blocking calcineurin activity impairs STIM1/ORAI1 puncta-like formation and cytoskeleton organization. In addition, we observe that calcineurin activity and its role in SOCE are both KSR2 dependent. |
| doi_str_mv | 10.1091/mbc.E13-05-0292 |
| format | Article |
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J.</contributor><creatorcontrib>Giurisato, E ; Gamberucci, A ; Ulivieri, C ; Marruganti, S ; Rossi, E ; Giacomello, E ; Randazzo, D ; Sorrentino, V ; Martin, Thomas F. J.</creatorcontrib><description>Store-operated calcium entry (SOCE) is the predominant Ca(2+) entry mechanism in nonexcitable cells and controls a variety of physiological and pathological processes. Although significant progress has been made in identifying the components required for SOCE, the molecular mechanisms underlying it are elusive. The present study provides evidence for a direct involvement of kinase suppressor of Ras 2 (KSR2) in SOCE. Using lymphocytes and fibroblasts from ksr2(-/-) mice and shKSR2-depleted cells, we find that KSR2 is critical for the elevation of cytosolic Ca(2+) concentration. Specifically, our results show that although it is dispensable for Ca(2+)-store depletion, KSR2 is required for optimal calcium entry. We observe that KSR2 deficiency affects stromal interaction molecule 1 (STIM1)/ORAI1 puncta formation, which is correlated with cytoskeleton disorganization. Of interest, we find that KSR2-associated calcineurin is crucial for SOCE. Blocking calcineurin activity impairs STIM1/ORAI1 puncta-like formation and cytoskeleton organization. In addition, we observe that calcineurin activity and its role in SOCE are both KSR2 dependent.</description><identifier>ISSN: 1059-1524</identifier><identifier>EISSN: 1939-4586</identifier><identifier>DOI: 10.1091/mbc.E13-05-0292</identifier><identifier>PMID: 24672054</identifier><language>eng</language><publisher>United States: The American Society for Cell Biology</publisher><subject>Animals ; Calcineurin - metabolism ; Calcium - metabolism ; Calcium Channels - metabolism ; Cell Nucleus - drug effects ; Cell Nucleus - metabolism ; Cercopithecus aethiops ; COS Cells ; Cytoskeleton - drug effects ; Cytoskeleton - metabolism ; Gene Knockout Techniques ; HeLa Cells ; Humans ; Intracellular Space - drug effects ; Intracellular Space - metabolism ; Lymphocytes - drug effects ; Lymphocytes - metabolism ; Membrane Proteins - metabolism ; Mice ; Neoplasm Proteins - metabolism ; NFATC Transcription Factors - metabolism ; ORAI1 Protein ; Protein Transport - drug effects ; Protein-Serine-Threonine Kinases - deficiency ; Protein-Serine-Threonine Kinases - metabolism ; Stromal Interaction Molecule 1 ; Thapsigargin - pharmacology</subject><ispartof>Molecular biology of the cell, 2014-06, Vol.25 (11), p.1769-1781</ispartof><rights>2014 Giurisato et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).</rights><rights>2014 Giurisato This article is distributed by The American Society for Cell Biology under license from the author(s). 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Using lymphocytes and fibroblasts from ksr2(-/-) mice and shKSR2-depleted cells, we find that KSR2 is critical for the elevation of cytosolic Ca(2+) concentration. Specifically, our results show that although it is dispensable for Ca(2+)-store depletion, KSR2 is required for optimal calcium entry. We observe that KSR2 deficiency affects stromal interaction molecule 1 (STIM1)/ORAI1 puncta formation, which is correlated with cytoskeleton disorganization. Of interest, we find that KSR2-associated calcineurin is crucial for SOCE. Blocking calcineurin activity impairs STIM1/ORAI1 puncta-like formation and cytoskeleton organization. In addition, we observe that calcineurin activity and its role in SOCE are both KSR2 dependent.</description><subject>Animals</subject><subject>Calcineurin - metabolism</subject><subject>Calcium - metabolism</subject><subject>Calcium Channels - metabolism</subject><subject>Cell Nucleus - drug effects</subject><subject>Cell Nucleus - metabolism</subject><subject>Cercopithecus aethiops</subject><subject>COS Cells</subject><subject>Cytoskeleton - drug effects</subject><subject>Cytoskeleton - metabolism</subject><subject>Gene Knockout Techniques</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Intracellular Space - drug effects</subject><subject>Intracellular Space - metabolism</subject><subject>Lymphocytes - drug effects</subject><subject>Lymphocytes - metabolism</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Neoplasm Proteins - metabolism</subject><subject>NFATC Transcription Factors - metabolism</subject><subject>ORAI1 Protein</subject><subject>Protein Transport - drug effects</subject><subject>Protein-Serine-Threonine Kinases - deficiency</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Stromal Interaction Molecule 1</subject><subject>Thapsigargin - pharmacology</subject><issn>1059-1524</issn><issn>1939-4586</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUtLAzEUhYMovtfuJEtdRPOcJhtBStWiUrB1HTKZGx2ZR01mxP57p77Q1blwv3vugYPQEaNnjBp2Xuf-bMIEoYpQbvgG2mVGGCKVzjaHmSpDmOJyB-2l9EIpkzIbbaMdPginSu4iv3gGfDt_4MS7ypcN9LFssG_rZQXvOMJTX7kOEp4vpveMzB4upwwXq8bVpU_YNQVOXRuBtEuIA1fgT5e-xtB0cYVP5rPx5PQAbQVXJTj81n30eDVZjG_I3ex6Or68I14K05EAIeecs0wHbbQRQWtVaCnywjjhlRrlWnHDVPBZMLnPMy18RqkxMngjQIp9dPHlu-zzGgq_zuAqu4xl7eLKtq60_zdN-Wyf2jcrqdCKisHg5Nsgtq89pM7WZfJQVa6Btk-WKUGN4tyMBvT8C_WxTSlC-H3DqF1XY4dqLDBhqbLraoaL47_pfvmfLsQHqn2KTQ</recordid><startdate>201406</startdate><enddate>201406</enddate><creator>Giurisato, E</creator><creator>Gamberucci, A</creator><creator>Ulivieri, C</creator><creator>Marruganti, S</creator><creator>Rossi, E</creator><creator>Giacomello, E</creator><creator>Randazzo, D</creator><creator>Sorrentino, V</creator><general>The American Society for Cell 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><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201406</creationdate><title>The KSR2-calcineurin complex regulates STIM1-ORAI1 dynamics and store-operated calcium entry (SOCE)</title><author>Giurisato, E ; Gamberucci, A ; Ulivieri, C ; Marruganti, S ; Rossi, E ; Giacomello, E ; Randazzo, D ; Sorrentino, V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-fefb222168f89893f885d843bd9a3c557b852915fc6f9bcb683c600994fc93e43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Calcineurin - metabolism</topic><topic>Calcium - metabolism</topic><topic>Calcium Channels - metabolism</topic><topic>Cell Nucleus - drug effects</topic><topic>Cell Nucleus - metabolism</topic><topic>Cercopithecus aethiops</topic><topic>COS Cells</topic><topic>Cytoskeleton - drug effects</topic><topic>Cytoskeleton - metabolism</topic><topic>Gene Knockout Techniques</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Intracellular Space - drug effects</topic><topic>Intracellular Space - metabolism</topic><topic>Lymphocytes - drug effects</topic><topic>Lymphocytes - metabolism</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Neoplasm Proteins - metabolism</topic><topic>NFATC Transcription Factors - metabolism</topic><topic>ORAI1 Protein</topic><topic>Protein Transport - drug effects</topic><topic>Protein-Serine-Threonine Kinases - deficiency</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Stromal Interaction Molecule 1</topic><topic>Thapsigargin - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Giurisato, E</creatorcontrib><creatorcontrib>Gamberucci, A</creatorcontrib><creatorcontrib>Ulivieri, C</creatorcontrib><creatorcontrib>Marruganti, S</creatorcontrib><creatorcontrib>Rossi, E</creatorcontrib><creatorcontrib>Giacomello, E</creatorcontrib><creatorcontrib>Randazzo, D</creatorcontrib><creatorcontrib>Sorrentino, V</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular biology of the cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Giurisato, E</au><au>Gamberucci, A</au><au>Ulivieri, C</au><au>Marruganti, S</au><au>Rossi, E</au><au>Giacomello, E</au><au>Randazzo, D</au><au>Sorrentino, V</au><au>Martin, Thomas F. J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The KSR2-calcineurin complex regulates STIM1-ORAI1 dynamics and store-operated calcium entry (SOCE)</atitle><jtitle>Molecular biology of the cell</jtitle><addtitle>Mol Biol Cell</addtitle><date>2014-06</date><risdate>2014</risdate><volume>25</volume><issue>11</issue><spage>1769</spage><epage>1781</epage><pages>1769-1781</pages><issn>1059-1524</issn><eissn>1939-4586</eissn><abstract>Store-operated calcium entry (SOCE) is the predominant Ca(2+) entry mechanism in nonexcitable cells and controls a variety of physiological and pathological processes. Although significant progress has been made in identifying the components required for SOCE, the molecular mechanisms underlying it are elusive. The present study provides evidence for a direct involvement of kinase suppressor of Ras 2 (KSR2) in SOCE. 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| subjects | Animals Calcineurin - metabolism Calcium - metabolism Calcium Channels - metabolism Cell Nucleus - drug effects Cell Nucleus - metabolism Cercopithecus aethiops COS Cells Cytoskeleton - drug effects Cytoskeleton - metabolism Gene Knockout Techniques HeLa Cells Humans Intracellular Space - drug effects Intracellular Space - metabolism Lymphocytes - drug effects Lymphocytes - metabolism Membrane Proteins - metabolism Mice Neoplasm Proteins - metabolism NFATC Transcription Factors - metabolism ORAI1 Protein Protein Transport - drug effects Protein-Serine-Threonine Kinases - deficiency Protein-Serine-Threonine Kinases - metabolism Stromal Interaction Molecule 1 Thapsigargin - pharmacology |
| title | The KSR2-calcineurin complex regulates STIM1-ORAI1 dynamics and store-operated calcium entry (SOCE) |
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