{{Short description|Mammalian protein found in Homo sapiens}}{{Technical|date=July 2024}} {{Redirect|Leukocyte common antigen|other uses|LCA (disambiguation){{!}}LCA}} {{For|non-human gp180|Gp180 (disambiguation){{!}}Gp180}} {{Infobox_gene}} {{cs1 config|name-list-style=vanc|display-authors=6}} '''Protein tyrosine phosphatase, receptor type, C''' also known as '''PTPRC''' is an enzyme that, in humans, is encoded by the ''PTPRC'' gene.<ref name="pmid2169617">{{cite journal | vauthors = Kaplan R, Morse B, Huebner K, Croce C, Howk R, Ravera M, Ricca G, Jaye M, Schlessinger J | title = Cloning of three human tyrosine phosphatases reveals a multigene family of receptor-linked protein-tyrosine-phosphatases expressed in brain | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 18 | pages = 7000–7004 | date = September 1990 | pmid = 2169617 | pmc = 54670 | doi = 10.1073/pnas.87.18.7000 | doi-access = free | bibcode = 1990PNAS...87.7000K }}</ref> PTPRC is also known as '''CD45''' antigen (CD stands for cluster of differentiation), which was originally called '''leukocyte common antigen''' ('''LCA''').<ref name="entrez">{{cite web | title = Entrez Gene: PTPRC protein tyrosine phosphatase, receptor type, C| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=5788}}</ref>
PTPRC is a critical enzyme involved in regulating immune cell function. PTPRC is a transmembrane protein tyrosine phosphatase expressed on the surface of all nucleated hematopoietic cells, particularly lymphocytes. It plays a key role in the activation and differentiation of T cells, B cells, and other immune cells by modulating signaling pathways. It functions by dephosphorylating specific tyrosine residues on target proteins, thereby controlling various signaling processes essential for immune response and homeostasis.<ref name="pmid12414720" /><ref name="pmid2523715">{{cite journal | vauthors = Thomas ML | title = The leukocyte common antigen family | journal = Annual Review of Immunology | volume = 7 | issue = | pages = 339–69 | date = 1989 | pmid = 2523715 | doi = 10.1146/annurev.iy.07.040189.002011 }}</ref>
== Function ==
The protein product of this gene, best known as CD45, is a member of the protein tyrosine phosphatase (PTP) family. PTPs are signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. CD45 contains an extracellular domain, a single transmembrane segment, and two tandem intracytoplasmic catalytic domains, and thus belongs to the receptor type PTP family.{{cn|date=November 2020}}
CD45 is a type I transmembrane protein that is present in various isoforms on all differentiated hematopoietic cells (except erythrocytes and plasma cells).<ref name="pmid16423050">{{cite journal | vauthors = Holmes N | title = CD45: all is not yet crystal clear | journal = Immunology | volume = 117 | issue = 2 | pages = 145–155 | date = February 2006 | pmid = 16423050 | pmc = 1782222 | doi = 10.1111/j.1365-2567.2005.02265.x }}</ref> CD45 has been shown to be an essential regulator of T- and B-cell antigen receptor signalling. It functions through either direct interaction with components of the antigen receptor complexes via its extracellular domain (a form of co-stimulation), or by activating various Src family kinases required for the antigen receptor signaling via its cytoplasmic domain. CD45 also suppresses JAK kinases, and so functions as a negative regulator of cytokine receptor signaling.{{cn|date=November 2020}}
Many alternatively spliced transcripts variants of this gene, which encode distinct isoforms, have been reported.<ref name="entrez" /> Antibodies against the different isoforms of CD45 are used in routine immunohistochemistry to differentiate between immune cell types, as well as to differentiate between histological sections from lymphomas and carcinomas.<ref name=Leong>{{cite book| vauthors = Leong AS, Cooper K, Leong FJ |year=2003 |title=Manual of Diagnostic Cytology |edition=2nd |publisher=Greenwich Medical Media, Ltd. |pages=121–124 |isbn=1-84110-100-1 }}</ref>
== Isoforms ==
The CD45 protein family consists of multiple members that are all products of a single complex gene. This gene contains 34 exons, producing a massive protein with extracellular and cytoplasmic domains that are both unusually large. Exons 4, 5, and 6 (corresponding to protein regions A, B, and C) are alternatively spliced to generate up to eight different protein products featuring combinations of zero, one, two, or all three exons.<ref>{{cite web | title = Mini-review: CD45 characterization and Isoforms | url = https://www.bio-rad-antibodies.com/cd45-characterization-isoforms-structure-function-antibodies-minireview.html | publisher = Bio-Rad Laboratories, Inc. }}</ref>
CD45's large extracellular domain is highly glycosylated, and these eight isoforms allow wide variation in the structure of its side chains. The isoforms affect the protein's N-terminal region, which extends linearly out from the cell and bears the O-linked glycan chains. {{cn|date=November 2020}}
CD45 isoforms show cell-type and differentiation-stage specific expression, a pattern which is quite well conserved in mammals.<ref name="pmid12414720">{{cite journal | vauthors = Hermiston ML, Xu Z, Weiss A | title = CD45: a critical regulator of signaling thresholds in immune cells | journal = Annual Review of Immunology | volume = 21 | pages = 107–137 | date = 2003 | pmid = 12414720 | doi = 10.1146/annurev.immunol.21.120601.140946 }}</ref> These isoforms are often used as markers that identify and distinguish between different types of immune cells.
Naive T lymphocytes are typically positive for CD45RA, which includes only the A protein region. Activated and memory T lymphocytes express CD45RO, the shortest CD45 isoform, which lacks all three of the A, B, and C regions. This shortest isoform facilitates T cell activation.{{cn|date=November 2020}}
CD45R (also known as CD45RABC) contains all three possible exons. It is the longest protein and migrates at 200 kDa when isolated from T cells. B cells also express CD45R with heavier glycosylation, bringing the molecular weight to 220 kDa, hence the name B220 (B cell isoform of 220 kDa).
== Interactions ==
PTPRC has been shown to interact with: * GANAB,<ref name = "pmid9148925">{{cite journal | vauthors = Arendt CW, Ostergaard HL | title = Identification of the CD45-associated 116-kDa and 80-kDa proteins as the alpha- and beta-subunits of alpha-glucosidase II | journal = The Journal of Biological Chemistry | volume = 272 | issue = 20 | pages = 13117–13125 | date = May 1997 | pmid = 9148925 | doi = 10.1074/jbc.272.20.13117 | doi-access = free }}</ref><ref name = "pmid10921916">{{cite journal | vauthors = Baldwin TA, Gogela-Spehar M, Ostergaard HL | title = Specific isoforms of the resident endoplasmic reticulum protein glucosidase II associate with the CD45 protein-tyrosine phosphatase via a lectin-like interaction | journal = The Journal of Biological Chemistry | volume = 275 | issue = 41 | pages = 32071–32076 | date = October 2000 | pmid = 10921916 | doi = 10.1074/jbc.M003088200 | doi-access = free }}</ref><ref name = "pmid11564800">{{cite journal | vauthors = Baldwin TA, Ostergaard HL | title = Developmentally regulated changes in glucosidase II association with, and carbohydrate content of, the protein tyrosine phosphatase CD45 | journal = Journal of Immunology | volume = 167 | issue = 7 | pages = 3829–3835 | date = October 2001 | pmid = 11564800 | doi = 10.4049/jimmunol.167.7.3829 | doi-access = free }}</ref> * LYN,<ref name = "pmid7516335">{{cite journal | vauthors = Brown VK, Ogle EW, Burkhardt AL, Rowley RB, Bolen JB, Justement LB | title = Multiple components of the B cell antigen receptor complex associate with the protein tyrosine phosphatase, CD45 | journal = The Journal of Biological Chemistry | volume = 269 | issue = 25 | pages = 17238–17244 | date = June 1994 | pmid = 7516335 | doi = 10.1016/S0021-9258(17)32545-0 | doi-access = free }}</ref> * Lck,<ref name = "pmid8473339">{{cite journal | vauthors = Koretzky GA, Kohmetscher M, Ross S | title = CD45-associated kinase activity requires lck but not T cell receptor expression in the Jurkat T cell line | journal = The Journal of Biological Chemistry | volume = 268 | issue = 12 | pages = 8958–8964 | date = April 1993 | pmid = 8473339 | doi = 10.1016/S0021-9258(18)52965-3 | doi-access = free }}</ref><ref name = "pmid8576115">{{cite journal | vauthors = Ng DH, Watts JD, Aebersold R, Johnson P | title = Demonstration of a direct interaction between p56lck and the cytoplasmic domain of CD45 in vitro | journal = The Journal of Biological Chemistry | volume = 271 | issue = 3 | pages = 1295–1300 | date = January 1996 | pmid = 8576115 | doi = 10.1074/jbc.271.3.1295 | doi-access = free }}</ref> and * SKAP1.<ref name = "pmid11909961">{{cite journal | vauthors = Wu L, Fu J, Shen SH | title = SKAP55 coupled with CD45 positively regulates T-cell receptor-mediated gene transcription | journal = Molecular and Cellular Biology | volume = 22 | issue = 8 | pages = 2673–2686 | date = April 2002 | pmid = 11909961 | pmc = 133720 | doi = 10.1128/mcb.22.8.2673-2686.2002 }}</ref>
CD45 has been recently shown to interact with the HCMV UL11 protein. This interaction results in functional paralysis of T cells.<ref name="pmid22174689">{{cite journal | vauthors = Gabaev I, Steinbrück L, Pokoyski C, Pich A, Stanton RJ, Schwinzer R, Schulz TF, Jacobs R, Messerle M, Kay-Fedorov PC | title = The human cytomegalovirus UL11 protein interacts with the receptor tyrosine phosphatase CD45, resulting in functional paralysis of T cells | journal = PLOS Pathogens | volume = 7 | issue = 12 | article-number = e1002432 | date = December 2011 | pmid = 22174689 | pmc = 3234252 | doi = 10.1371/journal.ppat.1002432 | doi-access = free }}</ref> In addition, CD45 was shown to be the target of the species D adenovirus 19a E3/49K protein to inhibit the activation of NK and T cells.<ref name="pmid24218549">{{cite journal | vauthors = Windheim M, Southcombe JH, Kremmer E, Chaplin L, Urlaub D, Falk CS, Claus M, Mihm J, Braithwaite M, Dennehy K, Renz H, Sester M, Watzl C, Burgert HG | title = A unique secreted adenovirus E3 protein binds to the leukocyte common antigen CD45 and modulates leukocyte functions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 50 | pages = E4884–E4893 | date = December 2013 | pmid = 24218549 | pmc = 3864294 | doi = 10.1073/pnas.1312420110 | bibcode = 2013PNAS..110E4884W | doi-access = free }}</ref>
== Clinical importance ==
CD45 is a pan-leukocyte protein with tyrosine phosphatase activity involved in the regulation of signal transduction in hematopoiesis. CD45 does not colocalize with lipid rafts on murine and human non-transformed hematopoietic cells, but CD45 positioning within lipid rafts is modified during their oncogenic transformation to acute myeloid leukemia. CD45 colocalizes with lipid rafts on AML cells, which contributes to elevated GM-CSF signal intensity involved in proliferation of leukemic cells.{{cn|date=November 2020}}
Therapies for blood cancer, including acute myeloid leukemia, have been proposed based on the concept of genetically modifying the CD45 of healthy cells, among other cell markers, to be immune to a treatment that kills all normal CD45 cells, including the cancerous ones.<ref name=":0">{{Cite web |last=Mole |first=Beth |date=2024-07-15 |title=Genetic cloaking of healthy cells opens door to universal blood cancer therapy |url=https://arstechnica.com/science/2024/07/genetic-cloaking-of-healthy-cells-opens-door-to-universal-blood-cancer-therapy/ |access-date=2024-07-15 |website=Ars Technica |language=en-us}}</ref> An antibody-drug conjugate exists that kills specifically cells with unaltered CD45, and "shielded" cells with modified CD45 have been developed that evade this.<ref name=":0" /> Blood stem cell transplants would be used to replace the original healthy blood cells with modified stem cells, and then the treatment would be applied.<ref name=":0" />
== Use as a congenic marker ==
There are two identifiable alleles of CD45 in mice: CD45.1 (Ly5.1 historically) and CD45.2 (Ly5.2 historically).<ref name="url_JAX_NOTES">{{cite web | author = Mobraaten LE | url = http://jaxmice.jax.org/jaxnotes/archive/458b.html | title = JAX NOTES: Ly5 Gene Nomenclature, C57BL/6J and SJL/J - A History of Change | publisher = The Jackson Laboratory | year = 1994 | access-date = 2015-01-08 | archive-url = https://web.archive.org/web/20150108142539/http://jaxmice.jax.org/jaxnotes/archive/458b.html | archive-date = 2015-01-08 }}</ref> These two types of CD45 are believed to be functionally identical. As such, they are routinely used in scientific research to allow identification of cells. For instance, leukocytes can be transferred from a CD45.1 donor mouse, into a CD45.2 host mouse, and can be subsequently identified due to their expression of CD45.1. This technique is also routinely used when generating chimeras. An alternative system is the use of CD90 (Thy1) alleles, which CD90.1/CD90.2 system is used in the same manner as the CD45.1/CD45.2 system.{{cn|date=November 2020}}
In 2016 a new knock-in mouse was generated on the C57BL/6 background to be a perfect congenic strain.<ref>{{cite journal | vauthors = Mercier FE, Sykes DB, Scadden DT | title = Single Targeted Exon Mutation Creates a True Congenic Mouse for Competitive Hematopoietic Stem Cell Transplantation: The C57BL/6-CD45.1(STEM) Mouse | journal = Stem Cell Reports | volume = 6 | issue = 6 | pages = 985–992 | date = June 2016 | pmid = 27185283 | pmc = 4911492 | doi = 10.1016/j.stemcr.2016.04.010 }}</ref> This mouse, dubbed the CD45.1STEM mouse, differs from the C57BL/6 strain by a single base pair resulting in a single amino acid change that confers the difference in reactivity by the anti-CD45.1 and anti-CD45.2 antibodies. This strain was designed for competitive bone marrow transplantation assays and demonstrated perfect equivalence, unlike the previous standard, the "SJL" mouse, more formally known as Pep Boy.<ref>{{Cite web|title=002014 - B6.SJL-Ptprc Pepc/BoyJ|url=https://www.jax.org/strain/002014|access-date=2020-10-11|website=www.jax.org}}</ref> {{Clear}}
== References == {{reflist}}
==Bibliography== {{refbegin}} * {{cite journal | vauthors = Tchilian EZ, Beverley PC | title = CD45 in memory and disease | journal = Archivum Immunologiae et Therapiae Experimentalis | volume = 50 | issue = 2 | pages = 85–93 | year = 2002 | pmid = 12022705 }} * {{cite journal | vauthors = Ishikawa H, Tsuyama N, Abroun S, Liu S, Li FJ, Otsuyama K, Zheng X, Kawano MM | title = Interleukin-6, CD45 and the src-kinases in myeloma cell proliferation | journal = Leukemia & Lymphoma | volume = 44 | issue = 9 | pages = 1477–1481 | date = September 2003 | pmid = 14565647 | doi = 10.3109/10428190309178767 | s2cid = 19867177 }} * {{cite journal | vauthors = Stanton T, Boxall S, Bennett A, Kaleebu P, Watera C, Whitworth J, French N, Dawes R, Hill AV, Bodmer W, Beverley PC, Tchilian EZ | title = CD45 variant alleles: possibly increased frequency of a novel exon 4 CD45 polymorphism in HIV seropositive Ugandans | journal = Immunogenetics | volume = 56 | issue = 2 | pages = 107–110 | date = May 2004 | pmid = 15057492 | doi = 10.1007/s00251-004-0668-z | s2cid = 10179258 }} * {{cite journal | vauthors = Huntington ND, Tarlinton DM | title = CD45: direct and indirect government of immune regulation | journal = Immunology Letters | volume = 94 | issue = 3 | pages = 167–174 | date = July 2004 | pmid = 15275963 | doi = 10.1016/j.imlet.2004.05.011 }} * {{cite web | url = http://www.bio.davidson.edu/courses/immunology/Students/spring2006/Jameson/CD45.html | title = CD45 | author = Jameson R | year = 2006 | work = Immunology course for undergraduates | publisher = Davidson College | access-date = 2011-10-24 }} {{refend}}
== External links == * {{PDBe-KB2|P08575|Receptor-type tyrosine-protein phosphatase C}}
{{PDB Gallery|geneid=5788}} {{Clusters of differentiation}} {{Protein tyrosine phosphatases}}
Category:Clusters of differentiation