ID FLOWR_DROME Reviewed; 194 AA. AC Q95T12; Q8IQM8; Q9VUU2; DT 24-NOV-2009, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 02-OCT-2024, entry version 146. DE RecName: Full=Calcium channel flower {ECO:0000303|PubMed:19737521}; DE Short=3L5 {ECO:0000303|PubMed:19737521}; GN Name=fwe; Synonyms=flower; ORFNames=CG6151; OS Drosophila melanogaster (Fruit fly). OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota; OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea; OC Drosophilidae; Drosophila; Sophophora. OX NCBI_TaxID=7227; RN [1] {ECO:0000312|EMBL:AAN11767.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=Berkeley; RX PubMed=10731132; DOI=10.1126/science.287.5461.2185; RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D., RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F., RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N., RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C., RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C., RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A., RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A., RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V., RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J., RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E., RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B., RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I., RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C., RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S., RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M., RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M., RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D., RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F., RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D., RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A., RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C., RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C., RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L., RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R., RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V., RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F., RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J., RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R., RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y., RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T., RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S., RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W., RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M., RA Venter J.C.; RT "The genome sequence of Drosophila melanogaster."; RL Science 287:2185-2195(2000). RN [2] {ECO:0000305, ECO:0000312|EMBL:AAN11767.1} RP GENOME REANNOTATION, AND ALTERNATIVE SPLICING. RC STRAIN=Berkeley; RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083; RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S., RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E., RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P., RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A., RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M., RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.; RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic RT review."; RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002). RN [3] {ECO:0000305, ECO:0000312|EMBL:AAL25424.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=Berkeley {ECO:0000312|EMBL:AAL25424.1}; RC TISSUE=Embryo {ECO:0000269|PubMed:12537569}; RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080; RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A., RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M., RA Celniker S.E.; RT "A Drosophila full-length cDNA resource."; RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002). RN [4] {ECO:0000305} RP FUNCTION, SUBUNIT (ISOFORM LOSE-A), SUBCELLULAR LOCATION, ALTERNATIVE RP SPLICING, DEVELOPMENTAL STAGE (ISOFORM LOSE-A), DISRUPTION PHENOTYPE, AND RP MUTAGENESIS OF GLU-79 AND GLY-128. RX PubMed=19737521; DOI=10.1016/j.cell.2009.06.033; RA Yao C.-K., Lin Y.Q., Ly C.V., Ohyama T., Haueter C.M., RA Moiseenkova-Bell V.Y., Wensel T.G., Bellen H.J.; RT "A synaptic vesicle-associated Ca2+ channel promotes endocytosis and RT couples exocytosis to endocytosis."; RL Cell 138:947-960(2009). RN [5] RP FUNCTION, SUBCELLULAR LOCATION (ISOFORM UBI), DEVELOPMENTAL STAGE (ISOFORM RP UBI), AND DISRUPTION PHENOTYPE. RX PubMed=20627080; DOI=10.1016/j.devcel.2010.05.010; RA Rhiner C., Lopez-Gay J.M., Soldini D., Casas-Tinto S., Martin F.A., RA Lombardia L., Moreno E.; RT "Flower forms an extracellular code that reveals the fitness of a cell to RT its neighbors in Drosophila."; RL Dev. Cell 18:985-998(2010). RN [6] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=20951347; DOI=10.1016/j.devcel.2010.09.004; RA Portela M., Casas-Tinto S., Rhiner C., Lopez-Gay J.M., Dominguez O., RA Soldini D., Moreno E.; RT "Drosophila SPARC is a self-protective signal expressed by loser cells RT during cell competition."; RL Dev. Cell 19:562-573(2010). RN [7] RP FUNCTION (ISOFORMS UBI AND LOSE-A), AND DEVELOPMENTAL STAGE (ISOFORMS UBI; RP LOSE-A AND LOSE-B). RX PubMed=23810538; DOI=10.1016/j.cub.2013.05.053; RA Merino M.M., Rhiner C., Portela M., Moreno E.; RT "'Fitness fingerprints' mediate physiological culling of unwanted neurons RT in Drosophila."; RL Curr. Biol. 23:1300-1309(2013). RN [8] RP FUNCTION, AND INDUCTION BY UV DAMAGE (ISOFORMS LOSE-A AND LOSE-B). RX PubMed=25601460; DOI=10.1016/j.cell.2014.12.017; RA Merino M.M., Rhiner C., Lopez-Gay J.M., Buechel D., Hauert B., Moreno E.; RT "Elimination of unfit cells maintains tissue health and prolongs RT lifespan."; RL Cell 160:461-476(2015). RN [9] RP FUNCTION, SUBCELLULAR LOCATION, INDUCTION BY TRAUMATIC BRAIN INJURY RP (ISOFORM LOSE-B), AND DEVELOPMENTAL STAGE (ISOFORMS LOSE-A AND LOSE-B). RX PubMed=25754635; DOI=10.1016/j.cub.2015.02.014; RA Moreno E., Fernandez-Marrero Y., Meyer P., Rhiner C.; RT "Brain regeneration in Drosophila involves comparison of neuronal RT fitness."; RL Curr. Biol. 25:955-963(2015). RN [10] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=28011160; DOI=10.1016/j.mod.2016.12.003; RA Nazario-Yepiz N.O., Riesgo-Escovar J.R.; RT "piragua encodes a zinc finger protein required for development in RT Drosophila."; RL Mech. Dev. 144:171-181(2017). RN [11] RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP GLU-79. RX PubMed=28414717; DOI=10.1371/journal.pbio.2000931; RA Yao C.K., Liu Y.T., Lee I.C., Wang Y.T., Wu P.Y.; RT "A Ca2+ channel differentially regulates Clathrin-mediated and activity- RT dependent bulk endocytosis."; RL PLoS Biol. 15:e2000931-e2000931(2017). RN [12] RP FUNCTION, AND TISSUE SPECIFICITY (ISOFORMS LOSE-A AND LOSE-B). RX PubMed=30590040; DOI=10.1016/j.celrep.2018.11.098; RA Coelho D.S., Schwartz S., Merino M.M., Hauert B., Topfel B., Tieche C., RA Rhiner C., Moreno E.; RT "Culling Less Fit Neurons Protects against Amyloid-beta-Induced Brain RT Damage and Cognitive and Motor Decline."; RL Cell Rep. 25:3661-3673(2018). RN [13] RP FUNCTION. RX PubMed=29288152; DOI=10.1083/jcb.201706053; RA Chang H.F., Mannebach S., Beck A., Ravichandran K., Krause E., RA Frohnweiler K., Fecher-Trost C., Schirra C., Pattu V., Flockerzi V., RA Rettig J.; RT "Cytotoxic granule endocytosis depends on the Flower protein."; RL J. Cell Biol. 217:667-683(2018). RN [14] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF GLU-79; 29-LYS--ARG-33 RP (ISOFORM LOSE-A); 146-LYS--LYS-150 (ISOFORM LOSE-A); LYS-95 (ISOFORM RP LOSE-A); LYS-100 (ISOFORM LOSE-A); LYS-105 (ISOFORM LOSE-A) AND RP 146-LYS--ARG-150 (ISOFORM LOSE-A). RX PubMed=33300871; DOI=10.7554/elife.60125; RA Li T.N., Chen Y.J., Lu T.Y., Wang Y.T., Lin H.C., Yao C.K.; RT "A positive feedback loop between Flower and PI(4,5)P2 at periactive zones RT controls bulk endocytosis in Drosophila."; RL Elife 9:0-0(2020). RN [15] RP FUNCTION, SUBCELLULAR LOCATION (ISOFORMS UBI; LOSE-A AND LOSE-B), RP INTERACTION WITH DALLY AND MAGU, TISSUE SPECIFICITY, AND DISRUPTION RP PHENOTYPE. RX PubMed=35301437; DOI=10.1038/s41556-022-00858-3; RA Merino M.M., Seum C., Dubois M., Gonzalez-Gaitan M.; RT "A role for Flower and cell death in controlling morphogen gradient RT scaling."; RL Nat. Cell Biol. 24:424-433(2022). CC -!- FUNCTION: Transmembrane protein which mediates synaptic endocytosis, CC fitness-based cell culling, neuronal culling, morphogen gradient CC scaling, and calcium transport (PubMed:20627080, PubMed:23810538, CC PubMed:25601460, PubMed:28011160, PubMed:33300871, PubMed:35301437). CC Regulates synaptic endocytosis and hence couples exo- with endocytosis CC (PubMed:19737521, PubMed:28414717, PubMed:29288152, PubMed:33300871). CC Controls two major modes of synaptic vesicle (SV) endocytosis in the CC synaptic boutons of neuromuscular junctions (NMJs); Ca(2+) channel- CC independent Clathrin-mediated endocytosis (CME) in response to mild CC stimulation, and Ca(2+) channel-dependent activity-dependent bulk CC endocytosis (ADBE) in response to strong stimulation (PubMed:28414717, CC PubMed:33300871). Functions in ADBE and subsequent SV reformation from CC bulk endosomes by initiating Ca(2+) channel-dependent CC phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) CC compartmentalization in synaptic boutons (PubMed:28414717, CC PubMed:33300871). There it acts at the periactive zone to provide the CC low Ca(2+) levels required to initiate Calcineurin activation and CC upregulate PtdIns(4,5)P2 (PubMed:33300871). Conversely PtdIns(4,5)P2 CC enhances fwe Ca(2+) channel-activity, establishing a positive feedback CC loop that induces PtdIns(4,5)P2 microdomain at the periactive zone CC (PubMed:33300871). These microdomains trigger bulk membrane CC invagination (i.e. ADBE) by triggering actin polymerization while also CC promoting localization of fwe to bulk endosomes, thereby removing the CC ADBE trigger to reduce endocytosis and prevent excess membrane uptake CC (PubMed:33300871). PtdIns(4,5)P2 then promotes SV reformation from the CC bulk endosomes, to coordinate ADBE and subsequent SV reformation CC (PubMed:33300871). Different combinations of the flower isoforms at the CC cell membrane are also required for the identification and elimination CC of suboptimal or supernumerary cells during development, regeneration, CC and adulthood (PubMed:20627080, PubMed:20951347, PubMed:23810538, CC PubMed:25601460, PubMed:28011160, PubMed:30590040). Required for the CC recognition and elimination of unfit cells in the developing wing CC during cell competition (PubMed:20627080). Also required for efficient CC identification and elimination of injured, damaged and/or dysfunctional CC neurons during regeneration of the adult brain (PubMed:25754635, CC PubMed:30590040). In the developing pupal retina, mediates the CC elimination of unwanted postmitotic neurons, including supernumerary CC photoreceptor neurons that form at the periphery of the retina and are CC contained within incomplete ommatidia units (PubMed:23810538). CC Downstream of the flower fitness fingerprints, cells identified as CC unwanted or unfit are eliminated via apoptosis through the expression CC of ahuizotl (azot) (PubMed:25601460, PubMed:30590040). However, the CC cells marked for elimination by the flower isoforms only undergo CC apoptosis if additional thresholds are met; (1) their neighboring CC fit/healthy cells express different levels of the fwe isoforms, and (2) CC the levels of the protective signal SPARC expressed by the loser or CC unwanted cells are unable to inhibit caspase activation CC (PubMed:20627080, PubMed:20951347, PubMed:23810538). These additional CC thresholds for flower-mediated apoptosis, allows useful cells to CC recover from transient and limited stress before they are unnecessarily CC eliminated (PubMed:20951347). Functions with dally and magu in a CC mechanism of scaling, which utilises apoptosis to ensure that the dpp CC morphogen gradient, which mediates organ growth, remains proportional CC to the size of the growing wing (PubMed:35301437). In this mechanism, CC fwe represses dally- and Magu-dependent activity in expanding the CC gradient, and dally/Magu inhibits fwe-dependent apoptosis to keep cell CC death rate low (PubMed:35301437). When the levels of these different CC proteins are optimally regulated the gradient correctly scales with CC organ growth but when this fails, fwe-mediated apoptosis is activated CC to trim the developing tissue to match the correct size of the gradient CC (PubMed:35301437). {ECO:0000269|PubMed:19737521, CC ECO:0000269|PubMed:20627080, ECO:0000269|PubMed:20951347, CC ECO:0000269|PubMed:23810538, ECO:0000269|PubMed:25601460, CC ECO:0000269|PubMed:25754635, ECO:0000269|PubMed:28011160, CC ECO:0000269|PubMed:28414717, ECO:0000269|PubMed:29288152, CC ECO:0000269|PubMed:30590040, ECO:0000269|PubMed:33300871, CC ECO:0000269|PubMed:35301437}. CC -!- FUNCTION: [Isoform Ubi]: Functions with the other flower isoforms to CC produce tissue-specific fitness fingerprints that identify unfit or fit CC cells during cell selection processes in order to maintain tissue CC health (PubMed:20627080, PubMed:25601460). In the wing imaginal disk, CC this isoform is highly expressed in healthy/normal cells but is down- CC regulated in cells with decreased fitness (PubMed:20627080). During CC cell competition, if levels of this isoform in unfit cells is lower CC than in the surrounding neighboring cells, the suboptimal cells are CC recognized as 'loser' cells, and undergo elimination via apoptosis to CC be replaced by the surrounding healthy 'winner' cell population CC (PubMed:20627080). {ECO:0000269|PubMed:20627080, CC ECO:0000269|PubMed:25601460}. CC -!- FUNCTION: [Isoform Lose-A]: Functions with the other flower isoforms to CC produce tissue-specific fitness fingerprints that identify unfit or fit CC cells during cell selection processes in order to maintain tissue CC health (PubMed:20627080, PubMed:25601460). In the wing imaginal disk, CC this isoform displays low levels of expression in healthy/normal cells CC but is up-regulated in cells with decreased fitness (PubMed:20627080, CC PubMed:25601460). During cell competition, if levels of this isoform in CC unfit cells is higher than in the surrounding neighboring cells, the CC suboptimal cells are recognized as 'loser' cells, and undergo CC elimination via apoptosis to be replaced by the surrounding healthy CC 'winner' cell population (PubMed:20627080, PubMed:25601460). CC {ECO:0000269|PubMed:20627080, ECO:0000269|PubMed:25601460}. CC -!- FUNCTION: [Isoform Lose-B]: Functions with the other flower isoforms to CC produce tissue-specific fitness fingerprints that identify unfit cells CC for cell selection processes during development, regeneration, and to CC maintain tissue health (PubMed:20627080, PubMed:25601460, CC PubMed:25754635, PubMed:30590040). During cell competition in certain CC tissues, marks suboptimal or damaged cells as 'loser' cells CC (PubMed:20627080, PubMed:25601460, PubMed:25754635, PubMed:30590040). CC In cells of the wing imaginal disk and damaged or dysfunctional neurons CC in the adult optic lobe, this isoform displays low to no expression in CC healthy/normal cells but is up-regulated in cells with decreased CC fitness or damage-affected neurons (PubMed:20627080, PubMed:25754635, CC PubMed:30590040). During cell competition, if levels of this isoform in CC unfit cells is higher than in the surrounding neighboring cells, the CC suboptimal cells are recognized as 'loser' cells, and undergo CC elimination via apoptosis to be replaced by the surrounding CC healthy/undamaged 'winner' cell population (PubMed:20627080, CC PubMed:25754635, PubMed:30590040). In the developing pupal retina, also CC required for the recognition and elimination of postmitotic neurons, CC including supernumerary photoreceptor neurons that form at the CC periphery of the retina and are contained within incomplete ommatidia CC units (PubMed:23810538). Activity at the peripheral retina is induced CC by the wg signaling pathway but, once activated, it promotes apoptosis CC of supernumerary photoreceptor neurons independently of wg signaling CC and snail function (PubMed:23810538). {ECO:0000269|PubMed:20627080, CC ECO:0000269|PubMed:23810538, ECO:0000269|PubMed:25601460, CC ECO:0000269|PubMed:25754635, ECO:0000269|PubMed:30590040}. CC -!- ACTIVITY REGULATION: Channel activity is inhibited by La(3+), which CC reduces Ca(2+) influx and thus inhibits it's function in promoting CC activity-dependent bulk endocytosis (ADBE) in response to high stimuli. CC {ECO:0000269|PubMed:28414717}. CC -!- SUBUNIT: [Isoform Ubi]: Associates with the dally/ magu complex. CC {ECO:0000269|PubMed:35301437}. CC -!- SUBUNIT: [Isoform Lose-A]: Homomultimer (PubMed:19737521). Associates CC with the dally/ magu complex (PubMed:35301437). CC {ECO:0000269|PubMed:19737521, ECO:0000269|PubMed:35301437}. CC -!- SUBUNIT: [Isoform Lose-B]: Associates with the dally/ magu complex. CC {ECO:0000269|PubMed:35301437}. CC -!- INTERACTION: CC Q95T12; Q95T12: fwe; NbExp=7; IntAct=EBI-169467, EBI-169467; CC Q95T12-2; Q95T12-2: fwe; NbExp=5; IntAct=EBI-2497181, EBI-2497181; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000255}; Multi-pass membrane CC protein {ECO:0000255}. Cytoplasmic vesicle, secretory vesicle, synaptic CC vesicle membrane {ECO:0000269|PubMed:19737521, CC ECO:0000269|PubMed:33300871}; Multi-pass membrane protein CC {ECO:0000269|PubMed:19737521}. Presynaptic cell membrane CC {ECO:0000269|PubMed:28414717, ECO:0000269|PubMed:33300871}. Endosome CC {ECO:0000269|PubMed:33300871}. Note=Upon fusion of the synaptic vesicle CC (SV) with the presynaptic membrane, protein transfers from the SV to CC the periactive zones where endocytosis is known to occur CC (PubMed:19737521, PubMed:28414717, PubMed:33300871). Upon high K(+) CC stimulation, expression levels in NMJ boutons are higher in bulk CC endosomes than in synaptic vesicles, suggesting that it is recycled to CC bulk endosomes after it activates ADBE (PubMed:33300871). CC {ECO:0000269|PubMed:19737521, ECO:0000269|PubMed:28414717, CC ECO:0000269|PubMed:33300871}. CC -!- SUBCELLULAR LOCATION: [Isoform Ubi]: Cell membrane CC {ECO:0000269|PubMed:20627080, ECO:0000269|PubMed:25754635, CC ECO:0000269|PubMed:35301437}; Multi-pass membrane protein CC {ECO:0000255}. Cytoplasmic vesicle, secretory vesicle, synaptic vesicle CC {ECO:0000269|PubMed:33300871}. Note=Localizes to the apico-lateral CC membranes in wing imaginal disks and salivary gland cells. CC {ECO:0000269|PubMed:20627080}. CC -!- SUBCELLULAR LOCATION: [Isoform Lose-A]: Cell membrane CC {ECO:0000269|PubMed:25754635, ECO:0000269|PubMed:35301437}; Multi-pass CC membrane protein {ECO:0000255}. Cytoplasmic vesicle, secretory vesicle, CC synaptic vesicle {ECO:0000269|PubMed:33300871}. CC -!- SUBCELLULAR LOCATION: [Isoform Lose-B]: Cell membrane CC {ECO:0000269|PubMed:25754635, ECO:0000269|PubMed:35301437}; Multi-pass CC membrane protein {ECO:0000255}. Cytoplasmic vesicle, secretory vesicle, CC synaptic vesicle {ECO:0000269|PubMed:33300871}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=Ubi {ECO:0000303|PubMed:20627080}; Synonyms=A CC {ECO:0000303|PubMed:19737521}; CC IsoId=Q95T12-1; Sequence=Displayed; CC Name=Lose-A {ECO:0000303|PubMed:20627080}; Synonyms=LoseA CC {ECO:0000303|PubMed:20627080}, B {ECO:0000303|PubMed:19737521}; CC IsoId=Q95T12-2; Sequence=VSP_053166; CC Name=Lose-B {ECO:0000303|PubMed:20627080}; Synonyms=LoseB CC {ECO:0000303|PubMed:20627080}, C {ECO:0000303|PubMed:19737521}; CC IsoId=Q95T12-3; Sequence=VSP_053165; CC -!- TISSUE SPECIFICITY: Detected in the imaginal wing disk (at protein CC level). {ECO:0000269|PubMed:35301437}. CC -!- TISSUE SPECIFICITY: [Isoform Ubi]: Detected throughout the adult brain, CC including the optic lobe but, at much lower levels of expression than CC isoform Lose-A. {ECO:0000269|PubMed:25754635}. CC -!- TISSUE SPECIFICITY: [Isoform Lose-A]: Detected in the optic lobe (at CC protein level) (PubMed:25754635). Detected throughout the adult brain, CC including the optic lobe (PubMed:25754635, PubMed:30590040). Expressed CC in damaged and undamaged optic lobe neurons (PubMed:25754635, CC PubMed:30590040). {ECO:0000269|PubMed:25754635, CC ECO:0000269|PubMed:30590040}. CC -!- TISSUE SPECIFICITY: [Isoform Lose-B]: Expressed in optic lobe neurons, CC with higher levels of expression in suboptimal neurons CC (PubMed:30590040). Specifically expressed in injury-damaged optic lobe CC neurons (PubMed:25754635). {ECO:0000269|PubMed:25754635, CC ECO:0000269|PubMed:30590040}. CC -!- DEVELOPMENTAL STAGE: [Isoform Ubi]: Detected in all imaginal disk cells CC and salivary gland cells (at protein level) (PubMed:20627080). In CC pupae, ubiquitously expressed in the retina including the neuronal CC layer (at protein level) (PubMed:23810538). CC {ECO:0000269|PubMed:20627080, ECO:0000269|PubMed:23810538}. CC -!- DEVELOPMENTAL STAGE: [Isoform Lose-A]: In pupal retinas, detected at 24 CC hr after pupal formation (APF) to 42 hr APF, where it is ubiquitously CC expressed throughout the retina including the neuronal layer (at CC protein level) (PubMed:23810538). Expressed in the neuropils of CC embryonic, larval, adult CNS, and R1-R6 terminals. Expression in the CC central nervous system (CNS) starts at embryonic stage 13 CC (PubMed:19737521). {ECO:0000269|PubMed:19737521, CC ECO:0000269|PubMed:23810538}. CC -!- DEVELOPMENTAL STAGE: [Isoform Lose-B]: In pupal retinas, specifically CC expressed at the periphery in photoreceptor neurons that are undergoing CC apoptosis (at protein level) (PubMed:23810538). Expression in the pupal CC retinas is not detected until 36 hr after pupal formation (APF) and is CC maintained until 44 hr APF; this is during the retina 'late cell death' CC event when peripheral ommatidia are being eliminated from the final CC structure (at protein level) (PubMed:23810538). CC {ECO:0000269|PubMed:23810538}. CC -!- INDUCTION: [Isoform Lose-A]: Induced in the midgut and adult brain by CC tissue damage caused by UV irradiation. {ECO:0000269|PubMed:25601460}. CC -!- INDUCTION: [Isoform Lose-B]: Induced in the midgut and adult brain by CC tissue damage caused by UV irradiation (PubMed:25601460). Up-regulated CC in optic lobe neurons that have been damaged by lesioning the optic CC lobe unilaterally causing penetrating traumatic brain injury CC (PubMed:25754635). {ECO:0000269|PubMed:25601460, CC ECO:0000269|PubMed:25754635}. CC -!- DISRUPTION PHENOTYPE: Lethal; mutants die either during the embryonic CC stage or the first instar larval stage (PubMed:28011160). Embryos CC frequently display head involution defects, some do not develop a CC cuticle and/or occasionally display dorsal closure defects CC (PubMed:28011160). The nervous system of embryos also displays CC developmental defects (PubMed:19737521, PubMed:20627080). In CC presynaptic terminals, intracellular resting calcium levels and CC endocytosis is impaired, whereas exocytosis is normal CC (PubMed:19737521). Boutons at the neuromuscular junctions exhibit a CC significant depletion in the number of synaptic vesicles CC (PubMed:19737521). There are numerous extra boutons which are often CC small, clustered, and flowery in nature (PubMed:19737521). Mutant nerve CC terminals display omega structures and collared pits (PubMed:19737521). CC RNAi-mediated knockdown in wing disks reduces cell apoptosis during CC Myc-mediated cell competition experiments (PubMed:28011160, CC PubMed:35301437). RNAi-mediated knockdown in the posterior compartment CC of the wing disk, has no effect on tissue growth under normal CC conditions however, growth is reduced in tissues undergoing Myc- CC mediated cell competition (PubMed:20627080). RNAi-mediated knockdown CC during Myc-mediated cell competition experiments, has no effect on up- CC regulation of SPARC in loser cells (PubMed:20951347). CC {ECO:0000269|PubMed:19737521, ECO:0000269|PubMed:20627080, CC ECO:0000269|PubMed:20951347, ECO:0000269|PubMed:28011160, CC ECO:0000269|PubMed:35301437}. CC -!- DISRUPTION PHENOTYPE: [Isoform Ubi]: RNAi-mediated knockdown in the CC posterior compartment of the wing disk, does not induce apoptosis and CC has no effect on compartment growth. {ECO:0000269|PubMed:20627080}. CC -!- MISCELLANEOUS: The name 'flower' derives from mutants that display CC numerous extra boutons that are small, clustered, and flowery in CC nature. {ECO:0000303|PubMed:19737521}. CC -!- SIMILARITY: Belongs to the calcium channel flower family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AE014296; AAF49581.1; -; Genomic_DNA. DR EMBL; AE014296; AAN11767.1; -; Genomic_DNA. DR EMBL; AE014296; AAN11768.1; -; Genomic_DNA. DR EMBL; AY060385; AAL25424.1; -; mRNA. DR RefSeq; NP_648804.1; NM_140547.5. [Q95T12-1] DR RefSeq; NP_730071.1; NM_168632.4. [Q95T12-3] DR RefSeq; NP_730072.1; NM_168633.4. [Q95T12-2] DR AlphaFoldDB; Q95T12; -. DR BioGRID; 65034; 24. DR IntAct; Q95T12; 27. DR STRING; 7227.FBpp0075297; -. DR TCDB; 1.A.55.1.2; the synaptic vesicle-associated ca(2+) channel, flower (flower) family. DR SwissPalm; Q95T12; -. DR PaxDb; 7227-FBpp0075297; -. DR DNASU; 39720; -. DR EnsemblMetazoa; FBtr0075541; FBpp0075296; FBgn0261722. [Q95T12-2] DR EnsemblMetazoa; FBtr0075542; FBpp0075297; FBgn0261722. [Q95T12-1] DR EnsemblMetazoa; FBtr0075543; FBpp0075298; FBgn0261722. [Q95T12-3] DR GeneID; 39720; -. DR KEGG; dme:Dmel_CG6151; -. DR UCSC; CG6151-RA; d. melanogaster. [Q95T12-1] DR UCSC; CG6151-RB; d. melanogaster. DR UCSC; CG6151-RC; d. melanogaster. DR AGR; FB:FBgn0261722; -. DR CTD; 39720; -. DR FlyBase; FBgn0261722; fwe. DR VEuPathDB; VectorBase:FBgn0261722; -. DR eggNOG; KOG4085; Eukaryota. DR GeneTree; ENSGT00390000000529; -. DR HOGENOM; CLU_108196_0_0_1; -. DR InParanoid; Q95T12; -. DR OMA; WYRWICK; -. DR OrthoDB; 5397038at2759; -. DR PhylomeDB; Q95T12; -. DR BioGRID-ORCS; 39720; 0 hits in 1 CRISPR screen. DR GenomeRNAi; 39720; -. DR PRO; PR:Q95T12; -. DR Proteomes; UP000000803; Chromosome 3L. DR Bgee; FBgn0261722; Expressed in wing disc and 31 other cell types or tissues. DR ExpressionAtlas; Q95T12; baseline and differential. DR GO; GO:0042995; C:cell projection; IEA:UniProtKB-KW. DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:FlyBase. DR GO; GO:0042734; C:presynaptic membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030672; C:synaptic vesicle membrane; IDA:UniProtKB. DR GO; GO:0005262; F:calcium channel activity; IDA:FlyBase. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0150008; P:bulk synaptic vesicle endocytosis; IMP:FlyBase. DR GO; GO:0070588; P:calcium ion transmembrane transport; IMP:FlyBase. DR GO; GO:0006816; P:calcium ion transport; IDA:FlyBase. DR GO; GO:0035212; P:cell competition in a multicellular organism; IMP:FlyBase. DR GO; GO:0150007; P:clathrin-dependent synaptic vesicle endocytosis; IMP:FlyBase. DR GO; GO:0046530; P:photoreceptor cell differentiation; IMP:UniProtKB. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:FlyBase. DR GO; GO:0099533; P:positive regulation of presynaptic cytosolic calcium concentration; IMP:FlyBase. DR GO; GO:0042981; P:regulation of apoptotic process; IMP:FlyBase. DR GO; GO:0048488; P:synaptic vesicle endocytosis; IMP:UniProtKB. DR GO; GO:0016192; P:vesicle-mediated transport; IBA:GO_Central. DR InterPro; IPR019365; TVP18/Ca-channel_flower. DR PANTHER; PTHR13314:SF2; CALCIUM CHANNEL FLOWER HOMOLOG; 1. DR PANTHER; PTHR13314; UNCHARACTERIZED; 1. DR Pfam; PF10233; Cg6151-P; 1. DR SMART; SM01077; Cg6151-P; 1. PE 1: Evidence at protein level; KW Alternative splicing; Calcium; Calcium channel; Calcium transport; KW Cell membrane; Cell projection; Cytoplasmic vesicle; Endocytosis; Endosome; KW Ion channel; Ion transport; Membrane; Reference proteome; Synapse; KW Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..194 FT /note="Calcium channel flower" FT /id="PRO_0000389234" FT TOPO_DOM 1..34 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 35..55 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 56..65 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 66..88 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 89..106 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 107..127 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 128..194 FT /note="Extracellular" FT /evidence="ECO:0000305" FT SITE 79 FT /note="Calcium ion selectivity" FT /evidence="ECO:0000269|PubMed:19737521" FT VAR_SEQ 147..194 FT /note="KASAEDMRAAAQQTFGGNTPAQTNDRAGIVNNAQPFSFTGAVGTDSNV -> FT NKHIFLVRNYI (in isoform Lose-B)" FT /evidence="ECO:0000303|PubMed:10731132, FT ECO:0000303|PubMed:19737521" FT /id="VSP_053165" FT VAR_SEQ 150..194 FT /note="AEDMRAAAQQTFGGNTPAQTNDRAGIVNNAQPFSFTGAVGTDSNV -> RED FT MAAAATSPTQMAGSQAGGQMQMGGDQHITLMEDPDVWRPT (in isoform Lose- FT A)" FT /evidence="ECO:0000303|PubMed:10731132, FT ECO:0000303|PubMed:19737521" FT /id="VSP_053166" FT MUTAGEN 79 FT /note="E->Q: Impaired Ca(2+) channel activity. Heterologous FT expression in salivary glands shows inhibition of calcium FT influx. Following strong stimulation that induces activity- FT dependent bulk endocytosis (ADBE), loses ability to promote FT the Ca(2+) channel-dependent formation of FT phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) FT microdomains at periactive zones in the synaptic boutons of FT larval NMJs. However, no effect on activating Clathrin- FT mediated endocytosis (CME) in NMJ boutons in response to FT mild stimulation." FT /evidence="ECO:0000269|PubMed:19737521, FT ECO:0000269|PubMed:28414717, ECO:0000269|PubMed:33300871" FT MUTAGEN 128 FT /note="G->D: In allele DB25; defect in synaptic FT transmission and homozygous lethal." FT /evidence="ECO:0000269|PubMed:19737521" FT REGION Q95T12-2:135..192 FT /note="Important for promoting apoptosis" FT /evidence="ECO:0000269|PubMed:20627080" FT MUTAGEN Q95T12-2:29..33 FT /note="KYGSR->AYGSA: Following high K+ stimulation, FT displays reduced formation of PtdIns(4,5)P2 microdomains at FT periactive zones and an impaired Ca2+ response in NMJ FT boutons, and decreased binding to phosphatidylinositol 4,5- FT bisphosphate (PtdIns(4,5)P2). Unable to rescue stimulation FT induced activity-dependent bulk endocytosis (ADBE) and FT synaptic vesicle replacement in mutants. No affect on FT localization to the presynaptic compartments of NMJ FT boutons. Severe decrease in binding to PtdIns(4,5)P2; when FT associated with A-95, A-100, A-105 and 146-A--A-150." FT /evidence="ECO:0000269|PubMed:33300871" FT MUTAGEN Q95T12-2:95 FT /note="E->A: Decreased binding to phosphatidylinositol 4,5- FT bisphosphate (PtdIns(4,5)P2); when associated with A-100, FT A-105 and 146-A--A-150. Severe decrease in binding to FT PtdIns(4,5)P2; when associated with 29-A--A-33, A-100, A- FT 105 and 146-A--A-150." FT /evidence="ECO:0000269|PubMed:33300871" FT MUTAGEN Q95T12-2:100 FT /note="K->A: Decreased binding to phosphatidylinositol 4,5- FT bisphosphate (PtdIns(4,5)P2); when associated with A-95, A- FT 105 and 146-A--A-150. Severe decrease in binding to FT PtdIns(4,5)P2; when associated with 29-A--A-33, A-95, A-105 FT and 146-A--A-150." FT /evidence="ECO:0000269|PubMed:33300871" FT MUTAGEN Q95T12-2:105 FT /note="R->A: Decreased binding to phosphatidylinositol 4,5- FT bisphosphate (PtdIns(4,5)P2); when associated with A-95, A- FT 100 and 146-A--A-150. Severe decrease in binding to FT PtdIns(4,5)P2; when associated with 29-A--A-33, A-95, A-100 FT and 146-A--A-150." FT /evidence="ECO:0000269|PubMed:33300871" FT MUTAGEN Q95T12-2:146..150 FT /note="KKASR->AAASA: Following high K+ stimuli, no effect FT on synaptic vesicle localization, regulation of presynaptic FT Ca(2+) concentration, induction of phosphatidylinositol FT 4,5-bisphosphate (PtdIns(4,5)P2) in NMJ boutons or FT activity-dependent bulk endocytosis (ADBE). Severe decrease FT in binding to phosphatidylinositol 4,5-bisphosphate FT (PtdIns(4,5)P2); when associated with 29-A--A-33, A-95, A- FT 100 and A-105." FT /evidence="ECO:0000269|PubMed:33300871" FT REGION Q95T12-3:135..157 FT /note="Important for promoting apoptosis" FT /evidence="ECO:0000269|PubMed:20627080" SQ SEQUENCE 194 AA; 20620 MW; 2D2817158AD73A57 CRC64; MSFAEKITGL LARPNQQDPI GPEQPWYLKY GSRLLGIVAA FFAILFGLWN VFSIITLSVS CLVAGILQMV AGFVVMLLEA PCCFVCFGQV NEIAEKVESK PLYFRAGLYI AMAIPPIILC FGLASLFGSG LIFGTGVVYG MMALGKKASA EDMRAAAQQT FGGNTPAQTN DRAGIVNNAQ PFSFTGAVGT DSNV //