PHAG1_MOUSE
ID PHAG1_MOUSE Reviewed; 429 AA.
AC Q3U1F9; Q8BFS1; Q9EQF3;
DT 20-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT 20-DEC-2005, sequence version 2.
DT 03-AUG-2022, entry version 130.
DE RecName: Full=Phosphoprotein associated with glycosphingolipid-enriched microdomains 1;
DE AltName: Full=Csk-binding protein;
DE AltName: Full=Transmembrane phosphoprotein Cbp;
GN Name=Pag1; Synonyms=Cbp, Pag;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10790433; DOI=10.1084/jem.191.9.1591;
RA Brdicka T., Pavlistova D., Bruyns E., Leo A., Korinek V., Angelisova P.,
RA Scherer J., Shevchenko A., Shevchenko A., Hilgert I., Cerny J., Drbal K.,
RA Kuramitsu Y., Horejsi V., Schraven B.;
RT "Phosphoprotein associated with glycosphingolipid-enriched microdomains
RT (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds
RT the protein tyrosine kinase csk and is involved in regulation of T cell
RT activation.";
RL J. Exp. Med. 191:1591-1604(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Spleen, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP INTERACTION WITH SLC9A3R1, IDENTIFICATION IN A COMPLEX WITH SLC9A3R1 AND
RP MSN, MUTAGENESIS OF LEU-429, SUBCELLULAR LOCATION, AND PHOSPHORYLATION.
RX PubMed=11777944; DOI=10.4049/jimmunol.168.2.541;
RA Itoh K., Sakakibara M., Yamasaki S., Takeuchi A., Arase H., Miyazaki M.,
RA Nakajima N., Okada M., Saito T.;
RT "Negative regulation of immune synapse formation by anchoring lipid raft to
RT cytoskeleton through Cbp-EBP50-ERM assembly.";
RL J. Immunol. 168:541-544(2002).
RN [4]
RP PHOSPHORYLATION AT TYR-314, INTERACTION WITH CSK, AND FUNCTION.
RX PubMed=12218089; DOI=10.4049/jimmunol.169.6.2813;
RA Yasuda K., Nagafuku M., Shima T., Okada M., Yagi T., Yamada T., Minaki Y.,
RA Kato A., Tani-Ichi S., Hamaoka T., Kosugi A.;
RT "Fyn is essential for tyrosine phosphorylation of Csk-binding
RT protein/phosphoprotein associated with glycolipid-enriched microdomains in
RT lipid rafts in resting T cells.";
RL J. Immunol. 169:2813-2817(2002).
RN [5]
RP PALMITOYLATION.
RX PubMed=12626544; DOI=10.4049/jimmunol.170.6.2932;
RA Van Laethem F., Liang X., Andris F., Urbain J., Vandenbranden M.,
RA Ruysschaert J.-M., Resh M.D., Stulnig T.M., Leo O.;
RT "Glucocorticoids alter the lipid and protein composition of membrane rafts
RT of a murine T cell hybridoma.";
RL J. Immunol. 170:2932-2939(2003).
RN [6]
RP PHOSPHORYLATION AT TYR-314, MUTAGENESIS OF TYR-314, INTERACTION WITH CSK,
RP SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=12612075; DOI=10.1128/mcb.23.6.2017-2028.2003;
RA Davidson D., Bakinowski M., Thomas M.L., Horejsi V., Veillette A.;
RT "Phosphorylation-dependent regulation of T-cell activation by PAG/Cbp, a
RT lipid raft-associated transmembrane adaptor.";
RL Mol. Cell. Biol. 23:2017-2028(2003).
RN [7]
RP FUNCTION, PHOSPHORYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=14645715; DOI=10.1073/pnas.2432139100;
RA Shima T., Nada S., Okada M.;
RT "Transmembrane phosphoprotein Cbp senses cell adhesion signaling mediated
RT by Src family kinase in lipid rafts.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:14897-14902(2003).
RN [8]
RP PHOSPHORYLATION AT TYR-314, AND INTERACTION WITH CSK.
RX PubMed=14967142; DOI=10.1016/s1097-2765(04)00050-4;
RA Zhang S.Q., Yang W., Kontaridis M.I., Bivona T.G., Wen G., Araki T.,
RA Luo J., Thompson J.A., Schraven B.L., Philips M.R., Neel B.G.;
RT "Shp2 regulates SRC family kinase activity and Ras/Erk activation by
RT controlling Csk recruitment.";
RL Mol. Cell 13:341-355(2004).
RN [9]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, FUNCTION, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=16166631; DOI=10.1128/mcb.25.19.8486-8495.2005;
RA Xu S., Huo J., Tan J.E.-L., Lam K.-P.;
RT "Cbp deficiency alters Csk localization in lipid rafts but does not affect
RT T-cell development.";
RL Mol. Cell. Biol. 25:8486-8495(2005).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-224, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Mast cell;
RX PubMed=17947660; DOI=10.4049/jimmunol.179.9.5864;
RA Cao L., Yu K., Banh C., Nguyen V., Ritz A., Raphael B.J., Kawakami Y.,
RA Kawakami T., Salomon A.R.;
RT "Quantitative time-resolved phosphoproteomic analysis of mast cell
RT signaling.";
RL J. Immunol. 179:5864-5876(2007).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-165; TYR-183; TYR-224 AND
RP SER-379, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-351 AND SER-379, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Kidney, Lung, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Negatively regulates TCR (T-cell antigen receptor)-mediated
CC signaling in T-cells and FCER1 (high affinity immunoglobulin epsilon
CC receptor)-mediated signaling in mast cells. Promotes CSK activation and
CC recruitment to lipid rafts, which results in LCK inhibition. Inhibits
CC immunological synapse formation by preventing dynamic arrangement of
CC lipid raft proteins. May be involved in cell adhesion signaling.
CC {ECO:0000269|PubMed:12218089, ECO:0000269|PubMed:12612075,
CC ECO:0000269|PubMed:14645715, ECO:0000269|PubMed:16166631}.
CC -!- SUBUNIT: When phosphorylated, interacts with CSK. Interacts with
CC SLC9A3R1/EBP50. In resting T-cells, part of a PAG1-SLC9A3R1-MSN complex
CC which is disrupted upon TCR activation. {ECO:0000269|PubMed:11777944,
CC ECO:0000269|PubMed:12218089, ECO:0000269|PubMed:12612075,
CC ECO:0000269|PubMed:14967142}.
CC -!- INTERACTION:
CC Q3U1F9; P41241: Csk; NbExp=9; IntAct=EBI-8468834, EBI-2553183;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11777944,
CC ECO:0000269|PubMed:12612075, ECO:0000269|PubMed:14645715,
CC ECO:0000269|PubMed:16166631}; Single-pass type III membrane protein
CC {ECO:0000269|PubMed:11777944, ECO:0000269|PubMed:12612075,
CC ECO:0000269|PubMed:14645715, ECO:0000269|PubMed:16166631}. Note=Present
CC in lipid rafts.
CC -!- TISSUE SPECIFICITY: Present in T-cells (at protein level).
CC {ECO:0000269|PubMed:16166631}.
CC -!- PTM: Palmitoylated. {ECO:0000269|PubMed:12626544}.
CC -!- PTM: Phosphorylated by FYN on Tyr-314 in resting T-cells; which
CC promotes interaction with CSK. Dephosphorylated by PTPRC/CD45 upon TCR
CC activation; which leads to CSK dissociation. May also be
CC dephosphorylated by PTPN11. Hyperphosphorylated in mast cells upon
CC FCER1 activation. {ECO:0000269|PubMed:11777944,
CC ECO:0000269|PubMed:12218089, ECO:0000269|PubMed:12612075,
CC ECO:0000269|PubMed:14645715, ECO:0000269|PubMed:14967142}.
CC -!- DISRUPTION PHENOTYPE: Mice are viable and do not show any developmental
CC defect up to 20 months of age. They have normal T-cell development and
CC normal T- and B-cell responses. {ECO:0000269|PubMed:16166631}.
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; AF250192; AAG44565.1; -; mRNA.
DR EMBL; AK156000; BAE33539.1; -; mRNA.
DR EMBL; AK040230; BAC30545.1; -; mRNA.
DR EMBL; AK089329; BAC40842.1; -; mRNA.
DR EMBL; AK172106; BAE42829.1; -; mRNA.
DR CCDS; CCDS17235.1; -.
DR RefSeq; NP_001181960.1; NM_001195031.1.
DR RefSeq; NP_444412.2; NM_053182.5.
DR RefSeq; XP_006530170.1; XM_006530107.1.
DR RefSeq; XP_011246453.1; XM_011248151.2.
DR AlphaFoldDB; Q3U1F9; -.
DR BMRB; Q3U1F9; -.
DR SMR; Q3U1F9; -.
DR BioGRID; 220469; 5.
DR IntAct; Q3U1F9; 120.
DR MINT; Q3U1F9; -.
DR STRING; 10090.ENSMUSP00000124529; -.
DR iPTMnet; Q3U1F9; -.
DR PhosphoSitePlus; Q3U1F9; -.
DR SwissPalm; Q3U1F9; -.
DR EPD; Q3U1F9; -.
DR jPOST; Q3U1F9; -.
DR MaxQB; Q3U1F9; -.
DR PaxDb; Q3U1F9; -.
DR PRIDE; Q3U1F9; -.
DR ProteomicsDB; 288136; -.
DR Antibodypedia; 1175; 369 antibodies from 35 providers.
DR DNASU; 94212; -.
DR Ensembl; ENSMUST00000108384; ENSMUSP00000104021; ENSMUSG00000027508.
DR Ensembl; ENSMUST00000161949; ENSMUSP00000124529; ENSMUSG00000027508.
DR GeneID; 94212; -.
DR KEGG; mmu:94212; -.
DR UCSC; uc008opc.2; mouse.
DR CTD; 55824; -.
DR MGI; MGI:2443160; Pag1.
DR VEuPathDB; HostDB:ENSMUSG00000027508; -.
DR eggNOG; ENOG502QUCZ; Eukaryota.
DR GeneTree; ENSGT00390000002061; -.
DR HOGENOM; CLU_051189_1_0_1; -.
DR InParanoid; Q3U1F9; -.
DR OMA; QCRDITR; -.
DR OrthoDB; 1104680at2759; -.
DR PhylomeDB; Q3U1F9; -.
DR TreeFam; TF336170; -.
DR Reactome; R-MMU-180292; GAB1 signalosome.
DR Reactome; R-MMU-202427; Phosphorylation of CD3 and TCR zeta chains.
DR BioGRID-ORCS; 94212; 4 hits in 72 CRISPR screens.
DR ChiTaRS; Pag1; mouse.
DR PRO; PR:Q3U1F9; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; Q3U1F9; protein.
DR Bgee; ENSMUSG00000027508; Expressed in pineal body and 252 other tissues.
DR ExpressionAtlas; Q3U1F9; baseline and differential.
DR Genevisible; Q3U1F9; MM.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0045121; C:membrane raft; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0042169; F:SH2 domain binding; ISO:MGI.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0035556; P:intracellular signal transduction; ISO:MGI.
DR GO; GO:0050868; P:negative regulation of T cell activation; IDA:HGNC-UCL.
DR GO; GO:0050863; P:regulation of T cell activation; ISO:MGI.
DR InterPro; IPR032748; PAG.
DR PANTHER; PTHR16322; PTHR16322; 1.
DR Pfam; PF15347; PAG; 1.
PE 1: Evidence at protein level;
KW Adaptive immunity; Cell membrane; Immunity; Lipoprotein; Membrane;
KW Palmitate; Phosphoprotein; Reference proteome; Signal-anchor;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..429
FT /note="Phosphoprotein associated with glycosphingolipid-
FT enriched microdomains 1"
FT /id="PRO_0000083339"
FT TOPO_DOM 1..17
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 18..38
FT /note="Helical; Signal-anchor for type III membrane
FT protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 39..429
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 46..69
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 113..134
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 263..350
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 314..317
FT /note="Interaction with CSK"
FT REGION 364..429
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 427..429
FT /note="Interaction with SLC9A3R1"
FT /evidence="ECO:0000269|PubMed:11777944"
FT COMPBIAS 46..61
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 378..418
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 52
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JM80"
FT MOD_RES 63
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JM80"
FT MOD_RES 107
FT /note="Phosphotyrosine; by LYN"
FT /evidence="ECO:0000250|UniProtKB:Q9JM80"
FT MOD_RES 165
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:19144319"
FT MOD_RES 183
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:19144319"
FT MOD_RES 224
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:17947660,
FT ECO:0007744|PubMed:19144319"
FT MOD_RES 226
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NWQ8"
FT MOD_RES 314
FT /note="Phosphotyrosine; by FYN"
FT /evidence="ECO:0000269|PubMed:12218089,
FT ECO:0000269|PubMed:12612075, ECO:0000269|PubMed:14967142"
FT MOD_RES 351
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 356
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q9NWQ8"
FT MOD_RES 379
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19144319,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 386
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q9NWQ8"
FT MOD_RES 414
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q9NWQ8"
FT LIPID 39
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT LIPID 42
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT MUTAGEN 314
FT /note="Y->F: Enhances TCR-mediated signaling."
FT /evidence="ECO:0000269|PubMed:12612075"
FT MUTAGEN 429
FT /note="L->A: Abolishes interaction with SLC9A3R1 and effect
FT on synapse formation."
FT /evidence="ECO:0000269|PubMed:11777944"
FT CONFLICT 58
FT /note="L -> P (in Ref. 1; AAG44565)"
FT /evidence="ECO:0000305"
FT CONFLICT 287
FT /note="H -> R (in Ref. 1; AAG44565)"
FT /evidence="ECO:0000305"
FT CONFLICT 360
FT /note="K -> R (in Ref. 2; BAE33539)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 429 AA; 46549 MW; F5A95257B4C4DADC CRC64;
MGPAGSVLSS GQMQMQMVLW GSLAAVAMFF LITFLVLLCS TCDREKKPRQ HSGDHENLMN
VPSDKDMFSH SATSLTTDAL ASSEQNGVLT NGDILSEDST LTCMQHYEEV QTSASDLLDS
QDSTGKAKCH QSRELPRIPP ENAVDEILTA RAADTELGPG VEGPYEVLKD SSSQENMVED
CLYETVKEIK EVADKGQGGK SKSTSALKEL QGAPMEGKAD FAEYASVDRN KKCRHSANAE
SILGTCSDLD EESPPPVPVK LLDENANLPQ EGGGQAEEQA AEGTGGHSKR FSSLSYKSRE
EDPTLTEEEI SAMYSSVNKP GQSAHKPGPC MKGPESACHS MKGLPQRSSS SCNDLYATVK
DFEKTPNSIS TLPPARRPSE EPEPDYEAIQ TLNREDEKVP LETNGHHVPK ESDYESIGDL
QQCRDVTRL
