title: The KSR2-calcineurin complex regulates STIM1-ORAI1 dynamics and store-operated calcium entry (SOCE).
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. 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.
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy giurisato2@unisi.it.
authors.forename: E
authors.initials: E
authors.lastname: Giurisato
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gamberucci
authors.affiliation: Department of Life Sciences, University of Siena, 53100 Siena, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ulivieri
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Marruganti
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Rossi
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Giacomello
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Randazzo
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Sorrentino
mesh_terms: D000818:Animals; D019556:COS Cells; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D000071740:ORAI1 Protein; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D000071737:Stromal Interaction Molecule 1; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D019284:Thapsigargin; C557409:KSR2 protein, human; C542241:KSR2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D019703:Calcineurin; D002118:Calcium