ID CD28_HUMAN Reviewed; 220 AA. AC P10747; A8KAC1; Q13964; Q52M23; Q70WG0; Q8NI54; Q8NI55; Q8NI56; Q8WXJ2; AC Q9BYV0; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1989, sequence version 1. DT 04-NOV-2026, entry version 234. DE RecName: Full=T-cell-specific surface glycoprotein CD28; DE AltName: Full=TP44; DE AltName: CD_antigen=CD28; DE Flags: Precursor; GN Name=CD28; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=2825196; DOI=10.1073/pnas.84.23.8573; RA Aruffo A., Seed B.; RT "Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression RT system."; RL Proc. Natl. Acad. Sci. U.S.A. 84:8573-8577(1987). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 3), AND ALTERNATIVE RP SPLICING. RX PubMed=2162892; DOI=10.4049/jimmunol.145.1.344; RA Lee K.P., Taylor C., Petryniak B., Turka L.A., June C.H., Thompson C.B.; RT "The genomic organization of the CD28 gene. Implications for the regulation RT of CD28 mRNA expression and heterogeneity."; RL J. Immunol. 145:344-352(1990). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5). RX PubMed=11916166; DOI=10.1016/s0198-8859(01)00354-8; RA Deshpande M., Venuprasad K., Parab P.B., Saha B., Mitra D.; RT "A novel CD28 mRNA variant and simultaneous presence of various CD28 mRNA RT isoforms in human T lymphocytes."; RL Hum. Immunol. 63:20-23(2002). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 4 AND 6), AND CHARACTERIZATION RP (ISOFORM 3). RC TISSUE=Peripheral blood T-cell; RX PubMed=11877290; DOI=10.1182/blood.v99.6.2138; RA Hanawa H., Ma Y., Mikolajczak S.A., Charles M.L., Yoshida T., Yoshida R., RA Strathdee C.A., Litchfield D.W., Ochi A.; RT "A novel costimulatory signaling in human T lymphocytes by a splice variant RT of CD28."; RL Blood 99:2138-2145(2002). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7). RA Gan S.U., Hare J., Krivoshchapov L., Hui K.M., Galea-Lauri J., Farzaneh F., RA Darling D.; RT "New human CD28 isoforms generated by a novel splicing event in the RT 5'UTR."; RL Submitted (NOV-2002) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Livingston R.J., Shaffer T., McFarland I., Nguyen C.P., Stanaway I.B., RA Rajkumar N., Johnson E.J., da Ponte S.H., Willa H., Ahearn M.O., RA Bertucci C., Acklestad J., Carroll A., Swanson J., Gildersleeve H.I., RA Nickerson D.A.; RL Submitted (OCT-2006) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Synovium, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-178 (ISOFORM 1). RX PubMed=11735222; DOI=10.1006/geno.2001.6655; RA Ling V., Wu P.W., Finnerty H.F., Agostino M.J., Graham J.R., Chen S., RA Jussiff J.M., Fisk G.J., Miller C.P., Collins M.; RT "Assembly and annotation of human chromosome 2q33 sequence containing the RT CD28, CTLA4, and ICOS gene cluster: analysis by computational, comparative, RT and microarray approaches."; RL Genomics 78:155-168(2001). RN [12] RP FUNCTION. RX PubMed=1650475; DOI=10.1073/pnas.88.15.6575; RA Gimmi C.D., Freeman G.J., Gribben J.G., Sugita K., Freedman A.S., RA Morimoto C., Nadler L.M.; RT "B-cell surface antigen B7 provides a costimulatory signal that induces T RT cells to proliferate and secrete interleukin 2."; RL Proc. Natl. Acad. Sci. U.S.A. 88:6575-6579(1991). RN [13] RP FUNCTION, PHOSPHORYLATION AT TYR-191, INTERACTION WITH GRB2 AND PIK3R1, AND RP MUTAGENESIS OF TYR-191. RX PubMed=7568038; DOI=10.1073/pnas.92.19.8891; RA Raab M., Cai Y.C., Bunnell S.C., Heyeck S.D., Berg L.J., Rudd C.E.; RT "p56Lck and p59Fyn regulate CD28 binding to phosphatidylinositol 3-kinase, RT growth factor receptor-bound protein GRB-2, and T cell-specific protein- RT tyrosine kinase ITK: implications for T-cell costimulation."; RL Proc. Natl. Acad. Sci. U.S.A. 92:8891-8895(1995). RN [14] RP FUNCTION. RX PubMed=8617933; DOI=10.4049/jimmunol.156.9.3133; RA Blotta M.H., Marshall J.D., DeKruyff R.H., Umetsu D.T.; RT "Cross-linking of the CD40 ligand on human CD4+ T lymphocytes generates a RT costimulatory signal that up-regulates IL-4 synthesis."; RL J. Immunol. 156:3133-3140(1996). RN [15] RP FUNCTION, AND INTERACTION WITH CD80 AND CD86. RX PubMed=12196291; DOI=10.1016/s1074-7613(02)00362-x; RA Collins A.V., Brodie D.W., Gilbert R.J., Iaboni A., Manso-Sancho R., RA Walse B., Stuart D.I., van der Merwe P.A., Davis S.J.; RT "The interaction properties of costimulatory molecules revisited."; RL Immunity 17:201-210(2002). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-209, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=15144186; DOI=10.1021/ac035352d; RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., RA Peters E.C.; RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from RT human T cells using immobilized metal affinity chromatography and tandem RT mass spectrometry."; RL Anal. Chem. 76:2763-2772(2004). RN [17] RP FUNCTION (ISOFORM 3), SUBCELLULAR LOCATION (ISOFORM 3), INTERACTION WITH RP CD40LG (ISOFORM 3), AND PHOSPHORYLATION (ISOFORM 3). RX PubMed=15067037; DOI=10.1084/jem.20031705; RA Mikolajczak S.A., Ma B.Y., Yoshida T., Yoshida R., Kelvin D.J., Ochi A.; RT "The modulation of CD40 ligand signaling by transmembrane CD28 splice RT variant in human T cells."; RL J. Exp. Med. 199:1025-1031(2004). RN [18] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-71 AND ASN-129. RC TISSUE=Leukemic T-cell; RX PubMed=19349973; DOI=10.1038/nbt.1532; RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., RA Schiess R., Aebersold R., Watts J.D.; RT "Mass-spectrometric identification and relative quantification of N-linked RT cell surface glycoproteins."; RL Nat. Biotechnol. 27:378-386(2009). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-189 AND TYR-191, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [20] RP FUNCTION, AND INTERACTION WITH PRKCQ. RX PubMed=21964608; DOI=10.1038/ni.2120; RA Kong K.F., Yokosuka T., Canonigo-Balancio A.J., Isakov N., Saito T., RA Altman A.; RT "A motif in the V3 domain of the kinase PKC-theta determines its RT localization in the immunological synapse and functions in T cells via RT association with CD28."; RL Nat. Immunol. 12:1105-1112(2011). RN [21] RP FUNCTION. RX PubMed=24665965; DOI=10.1042/bj20140040; RA Skaanland S.S., Moltu K., Berge T., Aandahl E.M., Tasken K.; RT "T-cell co-stimulation through the CD2 and CD28 co-receptors induces RT distinct signalling responses."; RL Biochem. J. 460:399-410(2014). RN [22] RP X-RAY CRYSTALLOGRAPHY IN COMPLEX WITH THE FAB FRAGMENT OF A MITOGENIC RP ANTIBODY, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-37 AND ASN-105. RX PubMed=15696168; DOI=10.1038/ni1170; RA Evans E.J., Esnouf R.M., Manso-Sancho R., Gilbert R.J., James J.R., Yu C., RA Fennelly J.A., Vowles C., Hanke T., Walse B., Hunig T., Sorensen P., RA Stuart D.I., Davis S.J.; RT "Crystal structure of a soluble CD28-Fab complex."; RL Nat. Immunol. 6:271-279(2005). RN [23] RP X-RAY CRYSTALLOGRAPHY IN COMPLEX WITH GRB2, AND INTERACTION WITH GRB2. RX PubMed=24098653; DOI=10.1371/journal.pone.0074482; RA Higo K., Ikura T., Oda M., Morii H., Takahashi J., Abe R., Ito N.; RT "High resolution crystal structure of the Grb2 SH2 domain with a RT phosphopeptide derived from CD28."; RL PLoS ONE 8:E74482-E74482(2013). RN [24] {ECO:0007744|PDB:7PPN} RP X-RAY CRYSTALLOGRAPHY, AND DEPHOSPHORYLATION BY PTPN11. RX PubMed=36114179; DOI=10.1038/s41467-022-32918-5; RA Zeke A., Takacs T., Sok P., Nemeth K., Kirsch K., Egri P., Poti A.L., RA Bento I., Tusnady G.E., Remenyi A.; RT "Structural insights into the pSer/pThr dependent regulation of the SHP2 RT tyrosine phosphatase in insulin and CD28 signaling."; RL Nat. Commun. 13:5439-5439(2022). RN [25] {ECO:0007744|PDB:7VU5} RP STRUCTURE BY NMR OF 148-188, SUBUNIT, SUBCELLULAR LOCATION, FUNCTION, AND RP MUTAGENESIS OF GLY-160 AND ALA-164. RX PubMed=35397202; DOI=10.1016/j.str.2022.03.004; RA Wu H., Cao R., Wen M., Xue H., OuYang B.; RT "Structural characterization of a dimerization interface in the CD28 RT transmembrane domain."; RL Structure 30:803-812.e5(2022). RN [26] RP VARIANT IMD123 ARG-18, INVOLVEMENT IN IMD123, AND CHARACTERIZATION OF RP VARIANT IMD123 ARG-18. RX PubMed=34214472; DOI=10.1016/j.cell.2021.06.004; RA Beziat V., Rapaport F., Hu J., Titeux M., Bonnet des Claustres M., RA Bourgey M., Griffin H., Bandet E., Ma C.S., Sherkat R., Rokni-Zadeh H., RA Louis D.M., Changi-Ashtiani M., Delmonte O.M., Fukushima T., Habib T., RA Guennoun A., Khan T., Bender N., Rahman M., About F., Yang R., Rao G., RA Rouzaud C., Li J., Shearer D., Balogh K., Al Ali F., Ata M., Dabiri S., RA Momenilandi M., Nammour J., Alyanakian M.A., Leruez-Ville M., Guenat D., RA Materna M., Marcot L., Vladikine N., Soret C., Vahidnezhad H., RA Youssefian L., Saeidian A.H., Uitto J., Catherinot E., Navabi S.S., RA Zarhrate M., Woodley D.T., Jeljeli M., Abraham T., Belkaya S., Lorenzo L., RA Rosain J., Bayat M., Lanternier F., Lortholary O., Zakavi F., Gros P., RA Orth G., Abel L., Pretet J.L., Fraitag S., Jouanguy E., Davis M.M., RA Tangye S.G., Notarangelo L.D., Marr N., Waterboer T., Langlais D., RA Doorbar J., Hovnanian A., Christensen N., Bossuyt X., Shahrooei M., RA Casanova J.L.; RT "Humans with inherited T cell CD28 deficiency are susceptible to skin RT papillomaviruses but are otherwise healthy."; RL Cell 184:3812-3828.e30(2021). CC -!- FUNCTION: Receptor that plays a role in T-cell activation, CC proliferation, survival and the maintenance of immune homeostasis CC (PubMed:1650475, PubMed:7568038). Functions not only as an amplifier of CC TCR signals but delivers unique signals that control intracellular CC biochemical events that alter the gene expression program of T-cells CC (PubMed:24665965). Stimulation upon engagement of its cognate ligands CC CD80 or CD86 increases proliferation and expression of various CC cytokines in particular IL2 production in both CD4(+) and CD8(+) T-cell CC subsets (PubMed:12196291, PubMed:1650475, PubMed:35397202). CC Mechanistically, ligation induces recruitment of protein kinase C- CC theta/PRKCQ and GRB2 leading to NF-kappa-B activation via both CC PI3K/Akt-dependent and -independent pathways (PubMed:21964608, CC PubMed:24665965, PubMed:7568038). In conjunction with TCR/CD3 ligation CC and CD40L costimulation, enhances the production of IL4 and IL10 in T- CC cells (PubMed:8617933). {ECO:0000269|PubMed:12196291, CC ECO:0000269|PubMed:1650475, ECO:0000269|PubMed:21964608, CC ECO:0000269|PubMed:24665965, ECO:0000269|PubMed:35397202, CC ECO:0000269|PubMed:7568038, ECO:0000269|PubMed:8617933}. CC -!- FUNCTION: [Isoform 3]: Enhances CD40L-mediated activation of NF-kappa-B CC and kinases MAPK8 and PAK2 in T-cells (PubMed:15067037). CC {ECO:0000269|PubMed:15067037}. CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:35397202). Interacts with CC DUSP14. Binds to CD80/B7-1 and CD86/B7-2/B70 (PubMed:12196291). CC Interacts with GRB2 (PubMed:24098653, PubMed:7568038). Interacts with CC PIK3R1 (PubMed:7568038). Interacts with PRKCQ (PubMed:21964608). CC {ECO:0000269|PubMed:12196291, ECO:0000269|PubMed:15696168, CC ECO:0000269|PubMed:21964608, ECO:0000269|PubMed:24098653, CC ECO:0000269|PubMed:35397202, ECO:0000269|PubMed:7568038}. CC -!- SUBUNIT: [Isoform 3]: Interacts with CD40LG. CC {ECO:0000269|PubMed:15067037}. CC -!- INTERACTION: CC P10747; P33681: CD80; NbExp=3; IntAct=EBI-4314301, EBI-1031024; CC P10747; P42081: CD86; NbExp=2; IntAct=EBI-4314301, EBI-1030956; CC P10747; P27986: PIK3R1; NbExp=10; IntAct=EBI-4314301, EBI-79464; CC P10747-1; P01552: entB; Xeno; NbExp=5; IntAct=EBI-15945088, EBI-1027464; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:35397202}; CC Single-pass type I membrane protein. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Cell surface CC {ECO:0000269|PubMed:15067037}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=7; CC Name=1; CC IsoId=P10747-1; Sequence=Displayed; CC Name=2; Synonyms=CD28-S2; CC IsoId=P10747-2; Sequence=VSP_002494; CC Name=3; Synonyms=CD28i; CC IsoId=P10747-3; Sequence=VSP_002495; CC Name=4; Synonyms=CD28-S1; CC IsoId=P10747-4; Sequence=VSP_002496; CC Name=5; CC IsoId=P10747-5; Sequence=VSP_002495, VSP_002497, VSP_002498; CC Name=6; Synonyms=CD28-S3; CC IsoId=P10747-6; Sequence=VSP_002495, VSP_002499; CC Name=7; CC IsoId=P10747-7; Sequence=VSP_047701; CC -!- TISSUE SPECIFICITY: Expressed in T-cells and plasma cells, but not in CC less mature B-cells. CC -!- PTM: Phosphorylated by LCK (PubMed:7568038). Dephosphorylated by PTPN11 CC (PubMed:36114179). {ECO:0000269|PubMed:36114179, CC ECO:0000269|PubMed:7568038}. CC -!- PTM: [Isoform 3]: Tyrosine phosphorylated induced by CD40LG. CC {ECO:0000269|PubMed:15067037}. CC -!- DISEASE: Immunodeficiency 123 with HPV-related verrucosis (IMD123) CC [MIM:620901]: An autosomal recessive immunologic disorder characterized CC by susceptibility to human papilloma virus (HPV) infections and the CC development of HPV-related common verrucosis in the first decade of CC life. In some patients with HPV2 infection, warts may progress to CC severe generalized hyperkeratotic cutaneous papillomatosis with CC cutaneous horns ('tree-man' phenotype). In patients with HPV4 CC infection, warts remains stable and may even regress with age. CC {ECO:0000269|PubMed:34214472}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. CC -!- WEB RESOURCE: Name=Wikipedia; Note=CD28 entry; CC URL="https://en.wikipedia.org/wiki/CD28"; 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; J02988; AAA60581.1; -; mRNA. DR EMBL; M37815; AAA51944.1; -; Genomic_DNA. DR EMBL; M37812; AAA51944.1; JOINED; Genomic_DNA. DR EMBL; M37813; AAA51944.1; JOINED; Genomic_DNA. DR EMBL; M37814; AAA51944.1; JOINED; Genomic_DNA. DR EMBL; M37815; AAA51945.1; -; Genomic_DNA. DR EMBL; M37812; AAA51945.1; JOINED; Genomic_DNA. DR EMBL; M37813; AAA51945.1; JOINED; Genomic_DNA. DR EMBL; M37814; AAA51945.1; JOINED; Genomic_DNA. DR EMBL; AJ295273; CAC29237.1; -; mRNA. DR EMBL; AF222341; AAF33792.1; -; mRNA. DR EMBL; AF222342; AAF33793.1; -; mRNA. DR EMBL; AF222343; AAF33794.1; -; mRNA. DR EMBL; AJ517504; CAD57003.1; -; mRNA. DR EMBL; EF064755; ABK41938.1; -; Genomic_DNA. DR EMBL; AK292986; BAF85675.1; -; mRNA. DR EMBL; AK313313; BAG36118.1; -; mRNA. DR EMBL; AC125238; AAY24123.1; -; Genomic_DNA. DR EMBL; CH471063; EAW70348.1; -; Genomic_DNA. DR EMBL; BC093698; AAH93698.1; -; mRNA. DR EMBL; BC112085; AAI12086.1; -; mRNA. DR EMBL; AF411057; AAL40931.1; -; Genomic_DNA. DR CCDS; CCDS2361.1; -. [P10747-1] DR CCDS; CCDS58749.1; -. [P10747-2] DR CCDS; CCDS92935.1; -. [P10747-7] DR PIR; A39983; RWHU28. DR RefSeq; NP_001230006.1; NM_001243077.2. [P10747-4] DR RefSeq; NP_001230007.1; NM_001243078.2. [P10747-2] DR RefSeq; NP_001397910.1; NM_001410981.1. [P10747-7] DR RefSeq; NP_006130.1; NM_006139.4. [P10747-1] DR PDB; 1YJD; X-ray; 2.70 A; C=17-152. DR PDB; 3WA4; X-ray; 1.35 A; B=189-196. DR PDB; 5AUL; X-ray; 1.10 A; B=189-196. DR PDB; 5GJH; X-ray; 1.20 A; B/D=189-196. DR PDB; 5GJI; X-ray; 0.90 A; B=189-196. DR PDB; 6O8D; X-ray; 3.55 A; C=19-136. DR PDB; 7PPN; X-ray; 1.90 A; B=183-198. DR PDB; 7VU5; NMR; -; A/B=148-188. DR PDB; 8S6Z; X-ray; 3.05 A; C/F=19-152. DR PDB; 8W2V; NMR; -; A=114-152. DR AlphaFoldDB; P10747; -. DR SMR; P10747; -. DR BioGRID; 107378; 27. DR CORUM; P10747; -. DR DIP; DIP-6043N; -. DR ELM; P10747; -. DR FunCoup; P10747; 343. DR IntAct; P10747; 28. DR NDEx; IQUERY-CP-CD28; 22 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000324890; -. DR ChEMBL; CHEMBL5191; -. DR DrugBank; DB06681; Belatacept. DR DrugBank; DB16687; Reltecimod. DR GuidetoPHARMACOLOGY; 2863; -. DR GlyCosmos; P10747; 5 sites, 4 glycans. DR GlyGen; P10747; 5 sites, 4 N-linked glycans (1 site). DR iPTMnet; P10747; -. DR PhosphoSitePlus; P10747; -. DR BioMuta; CD28; -. DR DMDM; 115973; -. DR MassIVE; P10747; -. DR PaxDb; 9606-ENSP00000324890; -. DR PeptideAtlas; P10747; -. DR ProteomicsDB; 52645; -. [P10747-1] DR ProteomicsDB; 52646; -. [P10747-2] DR ProteomicsDB; 52647; -. [P10747-3] DR ProteomicsDB; 52648; -. [P10747-4] DR ProteomicsDB; 68570; -. DR ABCD; P10747; 25 sequenced antibodies. DR Antibodypedia; 19958; 3411 antibodies from 54 providers. DR DNASU; 940; -. DR Ensembl; ENST00000324106.9; ENSP00000324890.7; ENSG00000178562.19. [P10747-1] DR Ensembl; ENST00000374481.8; ENSP00000363605.4; ENSG00000178562.19. [P10747-2] DR Ensembl; ENST00000458610.6; ENSP00000393648.2; ENSG00000178562.19. [P10747-7] DR GeneID; 940; -. DR KEGG; hsa:940; -. DR MANE-Select; ENST00000324106.9; ENSP00000324890.7; NM_006139.4; NP_006130.1. DR UCSC; uc002vah.6; human. [P10747-1] DR AGR; HGNC:1653; -. DR ClinPGx; PA26207; -. DR CTD; 940; -. DR DisGeNET; 940; -. DR GeneCards; CD28; -. DR HGNC; HGNC:1653; CD28. DR HPA; ENSG00000178562; Group enriched (lymphoid tissue, placenta). DR MalaCards; CD28; -. DR MIM; 186760; gene. DR MIM; 620901; phenotype. DR OpenTargets; ENSG00000178562; -. DR Orphanet; 2584; Classic mycosis fungoides. DR Orphanet; 3162; Sezary syndrome. DR VEuPathDB; HostDB:ENSG00000178562; -. DR eggNOG; ENOG502SAVP; Eukaryota. DR GeneTree; ENSGT00530000063873; -. DR HOGENOM; CLU_154699_0_0_1; -. DR InParanoid; P10747; -. DR OMA; AACINYW; -. DR OrthoDB; 8654606at2759; -. DR PAN-GO; P10747; 5 GO annotations based on evolutionary models. DR PhylomeDB; P10747; -. DR PathwayCommons; P10747; -. DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling. DR Reactome; R-HSA-164939; Nef mediated downregulation of CD28 cell surface expression. DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer. DR Reactome; R-HSA-389356; Co-stimulation by CD28. DR Reactome; R-HSA-389357; CD28 dependent PI3K/Akt signaling. DR Reactome; R-HSA-389359; CD28 dependent Vav1 pathway. DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. DR SignaLink; P10747; -. DR SIGNOR; P10747; -. DR Agora; ENSG00000178562; -. DR BioGRID-ORCS; 940; 21 hits in 1163 CRISPR screens. DR ChiTaRS; CD28; human. DR EvolutionaryTrace; P10747; -. DR GeneWiki; CD28; -. DR GenomeRNAi; 940; -. DR Pharos; P10747; Tbio. DR PRO; PR:P10747; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; P10747; protein. DR Bgee; ENSG00000178562; Expressed in lymph node and 99 other cell types or tissues. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0009897; C:external side of plasma membrane; IDA:MGI. DR GO; GO:0005886; C:plasma membrane; IDA:MGI. DR GO; GO:0098636; C:protein complex involved in cell adhesion; IDA:MGI. DR GO; GO:0015026; F:coreceptor activity; TAS:UniProtKB. DR GO; GO:0042802; F:identical protein binding; NAS:UniProtKB. DR GO; GO:0004888; F:transmembrane signaling receptor activity; IDA:UniProtKB. DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:UniProtKB. DR GO; GO:0006959; P:humoral immune response; TAS:UniProtKB. DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:UniProtKB. DR GO; GO:0001819; P:positive regulation of cytokine production; TAS:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB. DR GO; GO:0032733; P:positive regulation of interleukin-10 production; IDA:UniProtKB. DR GO; GO:0032743; P:positive regulation of interleukin-2 production; IDA:UniProtKB. DR GO; GO:0032753; P:positive regulation of interleukin-4 production; IDA:UniProtKB. DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IDA:UniProtKB. DR GO; GO:0042102; P:positive regulation of T cell proliferation; IDA:UniProtKB. DR GO; GO:0050862; P:positive regulation of T cell receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0045727; P:positive regulation of translation; NAS:UniProtKB. DR GO; GO:0045070; P:positive regulation of viral genome replication; NAS:UniProtKB. DR GO; GO:0045066; P:regulatory T cell differentiation; IDA:BHF-UCL. DR GO; GO:0042110; P:T cell activation; IDA:UniProt. DR GO; GO:0031295; P:T cell costimulation; IBA:GO_Central. DR GO; GO:0050852; P:T cell receptor signaling pathway; IBA:GO_Central. DR CDD; cd20925; IgV_CD28; 1. DR FunFam; 2.60.40.10:FF:000716; T-cell-specific surface glycoprotein CD28; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 1. DR IDEAL; IID00509; -. DR InterPro; IPR008093; CD28. DR InterPro; IPR040216; CTLA4/CD28. DR InterPro; IPR036179; Ig-like_dom_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR013106; Ig_V-set. DR PANTHER; PTHR11494; CYTOTOXIC T-LYMPHOCYTE PROTEIN; 1. DR PANTHER; PTHR11494:SF7; T-CELL-SPECIFIC SURFACE GLYCOPROTEIN CD28; 1. DR Pfam; PF15910; V-set_2; 1. DR PRINTS; PR01717; CD28ANTIGEN. DR SMART; SM00406; IGv; 1. DR SUPFAM; SSF48726; Immunoglobulin; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Disease variant; KW Disulfide bond; Glycoprotein; Immunoglobulin domain; Membrane; KW Phosphoprotein; Proteomics identification; Receptor; Reference proteome; KW Signal; Transmembrane; Transmembrane helix. FT SIGNAL 1..18 FT CHAIN 19..220 FT /note="T-cell-specific surface glycoprotein CD28" FT /id="PRO_0000014652" FT TOPO_DOM 19..152 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 153..179 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 180..220 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 28..137 FT /note="Ig-like V-type" FT REGION 198..220 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 189 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 191 FT /note="Phosphotyrosine; by LCK" FT /evidence="ECO:0000269|PubMed:7568038, FT ECO:0007744|PubMed:19690332" FT MOD_RES 209 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15144186" FT CARBOHYD 37 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15696168" FT CARBOHYD 71 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973" FT CARBOHYD 92 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 105 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15696168" FT CARBOHYD 129 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973" FT DISULFID 40..112 FT /evidence="ECO:0000269|PubMed:15696168" FT DISULFID 66..86 FT /evidence="ECO:0000269|PubMed:15696168" FT VAR_SEQ 1..17 FT /note="MLRLLLALNLFPSIQVT -> MPCGLSALIMCPKGMVAVVVAVDDGDSQALA FT (in isoform 7)" FT /evidence="ECO:0000303|Ref.5" FT /id="VSP_047701" FT VAR_SEQ 19..137 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11877290" FT /id="VSP_002494" FT VAR_SEQ 40..137 FT /note="CKYSYNLFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLG FT NESVTFYLQNLYVNQTDIYFCKIEVMYPPPYLDNEKSNGTIIHVKG -> W (in FT isoform 4)" FT /evidence="ECO:0000303|PubMed:11877290" FT /id="VSP_002496" FT VAR_SEQ 40..124 FT /note="CKYSYNLFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLG FT NESVTFYLQNLYVNQTDIYFCKIEVMYPPPYLD -> Y (in isoform 3, FT isoform 5 and isoform 6)" FT /evidence="ECO:0000303|PubMed:11877290, FT ECO:0000303|PubMed:11916166" FT /id="VSP_002495" FT VAR_SEQ 138..139 FT /note="KH -> EE (in isoform 5)" FT /evidence="ECO:0000303|PubMed:11916166" FT /id="VSP_002497" FT VAR_SEQ 140..220 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:11916166" FT /id="VSP_002498" FT VAR_SEQ 152..207 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|PubMed:11877290" FT /id="VSP_002499" FT VARIANT 18 FT /note="G -> R (in IMD123; likely pathogenic; the underlying FT nucleotide substitution affects splicing; patient-derived FT cells contain normally spliced transcripts with the FT missense variant and aberrant splice transcripts that FT probably undergo nonsense-mediated decay; significantly FT decreased CD28 mRNA levels in homozygous patient-derived T FT cells compared to controls; decreased function in T cell FT activation)" FT /evidence="ECO:0000269|PubMed:34214472" FT /id="VAR_089967" FT MUTAGEN 160 FT /note="G->Y: About 75% loss of IL2 release." FT /evidence="ECO:0000269|PubMed:35397202" FT MUTAGEN 164 FT /note="A->L: About 75% loss of IL2 release." FT /evidence="ECO:0000269|PubMed:35397202" FT MUTAGEN 191 FT /note="Y->F: Greatly reduced phosphorylation by LCK." FT /evidence="ECO:0000269|PubMed:7568038" FT STRAND 27..30 FT /evidence="ECO:0007829|PDB:1YJD" FT STRAND 35..43 FT /evidence="ECO:0007829|PDB:1YJD" FT STRAND 49..58 FT /evidence="ECO:0007829|PDB:1YJD" FT STRAND 64..74 FT /evidence="ECO:0007829|PDB:1YJD" FT STRAND 77..79 FT /evidence="ECO:0007829|PDB:1YJD" FT STRAND 81..83 FT /evidence="ECO:0007829|PDB:1YJD" FT STRAND 85..90 FT /evidence="ECO:0007829|PDB:1YJD" FT STRAND 92..101 FT /evidence="ECO:0007829|PDB:1YJD" FT HELIX 104..106 FT /evidence="ECO:0007829|PDB:1YJD" FT STRAND 108..121 FT /evidence="ECO:0007829|PDB:1YJD" FT STRAND 123..125 FT /evidence="ECO:0007829|PDB:1YJD" FT STRAND 131..134 FT /evidence="ECO:0007829|PDB:1YJD" FT HELIX 153..182 FT /evidence="ECO:0007829|PDB:7VU5" SQ SEQUENCE 220 AA; 25066 MW; 1D9B6552A5878D0F CRC64; MLRLLLALNL FPSIQVTGNK ILVKQSPMLV AYDNAVNLSC KYSYNLFSRE FRASLHKGLD SAVEVCVVYG NYSQQLQVYS KTGFNCDGKL GNESVTFYLQ NLYVNQTDIY FCKIEVMYPP PYLDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLVVVG GVLACYSLLV TVAFIIFWVR SKRSRLLHSD YMNMTPRRPG PTRKHYQPYA PPRDFAAYRS //