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PTPRC
Mammalian protein found in Homo sapiens

Protein tyrosine phosphatase, receptor type, C (PTPRC), also known as CD45 antigen, is an enzyme encoded by the PTPRC gene in humans. This transmembrane protein tyrosine phosphatase is expressed on all nucleated hematopoietic cells, especially lymphocytes. CD45 plays a crucial role in regulating immune cell functions by modulating signaling pathways during the activation and differentiation of T cells and B cells. It achieves this by dephosphorylating specific tyrosine residues on target proteins, thereby controlling processes essential for an effective immune response and maintaining homeostasis.

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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.

CD45 is a type I transmembrane protein that is present in various isoforms on all differentiated hematopoietic cells (except erythrocytes and plasma cells).5 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.

Many alternatively spliced transcripts variants of this gene, which encode distinct isoforms, have been reported.6 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.7

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.8

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.

CD45 isoforms show cell-type and differentiation-stage specific expression, a pattern which is quite well conserved in mammals.9 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.

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:

CD45 has been recently shown to interact with the HCMV UL11 protein. This interaction results in functional paralysis of T cells.17 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.18

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.

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.19 An antibody-drug conjugate exists that kills specifically cells with unaltered CD45, and "shielded" cells with modified CD45 have been developed that evade this.20 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.21

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).22 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.

In 2016 a new knock-in mouse was generated on the C57BL/6 background to be a perfect congenic strain.23 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.24

Bibliography

  • Tchilian EZ, Beverley PC (2002). "CD45 in memory and disease". Archivum Immunologiae Et Therapiae Experimentalis. 50 (2): 85–93. PMID 12022705.
  • Ishikawa H, Tsuyama N, Abroun S, Liu S, Li FJ, Otsuyama K, et al. (September 2003). "Interleukin-6, CD45 and the src-kinases in myeloma cell proliferation". Leukemia & Lymphoma. 44 (9): 1477–1481. doi:10.3109/10428190309178767. PMID 14565647. S2CID 19867177.
  • Stanton T, Boxall S, Bennett A, Kaleebu P, Watera C, Whitworth J, et al. (May 2004). "CD45 variant alleles: possibly increased frequency of a novel exon 4 CD45 polymorphism in HIV seropositive Ugandans". Immunogenetics. 56 (2): 107–110. doi:10.1007/s00251-004-0668-z. PMID 15057492. S2CID 10179258.
  • Huntington ND, Tarlinton DM (July 2004). "CD45: direct and indirect government of immune regulation". Immunology Letters. 94 (3): 167–174. doi:10.1016/j.imlet.2004.05.011. PMID 15275963.
  • Jameson R (2006). "CD45". Immunology course for undergraduates. Davidson College. Retrieved 2011-10-24.
  • Overview of all the structural information available in the PDB for UniProt: P08575 (Receptor-type tyrosine-protein phosphatase C) at the PDBe-KB.

References

  1. Kaplan R, Morse B, Huebner K, Croce C, Howk R, Ravera M, et al. (September 1990). "Cloning of three human tyrosine phosphatases reveals a multigene family of receptor-linked protein-tyrosine-phosphatases expressed in brain". Proceedings of the National Academy of Sciences of the United States of America. 87 (18): 7000–7004. Bibcode:1990PNAS...87.7000K. doi:10.1073/pnas.87.18.7000. PMC 54670. PMID 2169617. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC54670 ↩

  2. "Entrez Gene: PTPRC protein tyrosine phosphatase, receptor type, C". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5788 ↩

  3. Hermiston ML, Xu Z, Weiss A (2003). "CD45: a critical regulator of signaling thresholds in immune cells". Annual Review of Immunology. 21: 107–137. doi:10.1146/annurev.immunol.21.120601.140946. PMID 12414720. /wiki/Doi_(identifier) ↩

  4. Thomas ML (1989). "The leukocyte common antigen family". Annual Review of Immunology. 7: 339–69. doi:10.1146/annurev.iy.07.040189.002011. PMID 2523715. /wiki/Doi_(identifier) ↩

  5. Holmes N (February 2006). "CD45: all is not yet crystal clear". Immunology. 117 (2): 145–155. doi:10.1111/j.1365-2567.2005.02265.x. PMC 1782222. PMID 16423050. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1782222 ↩

  6. "Entrez Gene: PTPRC protein tyrosine phosphatase, receptor type, C". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5788 ↩

  7. Leong AS, Cooper K, Leong FJ (2003). Manual of Diagnostic Cytology (2nd ed.). Greenwich Medical Media, Ltd. pp. 121–124. ISBN 1-84110-100-1. 1-84110-100-1 ↩

  8. "Mini-review: CD45 characterization and Isoforms". Bio-Rad Laboratories, Inc. https://www.bio-rad-antibodies.com/cd45-characterization-isoforms-structure-function-antibodies-minireview.html ↩

  9. Hermiston ML, Xu Z, Weiss A (2003). "CD45: a critical regulator of signaling thresholds in immune cells". Annual Review of Immunology. 21: 107–137. doi:10.1146/annurev.immunol.21.120601.140946. PMID 12414720. /wiki/Doi_(identifier) ↩

  10. Arendt CW, Ostergaard HL (May 1997). "Identification of the CD45-associated 116-kDa and 80-kDa proteins as the alpha- and beta-subunits of alpha-glucosidase II". The Journal of Biological Chemistry. 272 (20): 13117–13125. doi:10.1074/jbc.272.20.13117. PMID 9148925. https://doi.org/10.1074%2Fjbc.272.20.13117 ↩

  11. Baldwin TA, Gogela-Spehar M, Ostergaard HL (October 2000). "Specific isoforms of the resident endoplasmic reticulum protein glucosidase II associate with the CD45 protein-tyrosine phosphatase via a lectin-like interaction". The Journal of Biological Chemistry. 275 (41): 32071–32076. doi:10.1074/jbc.M003088200. PMID 10921916. https://doi.org/10.1074%2Fjbc.M003088200 ↩

  12. Baldwin TA, Ostergaard HL (October 2001). "Developmentally regulated changes in glucosidase II association with, and carbohydrate content of, the protein tyrosine phosphatase CD45". Journal of Immunology. 167 (7): 3829–3835. doi:10.4049/jimmunol.167.7.3829. PMID 11564800. https://doi.org/10.4049%2Fjimmunol.167.7.3829 ↩

  13. Brown VK, Ogle EW, Burkhardt AL, Rowley RB, Bolen JB, Justement LB (June 1994). "Multiple components of the B cell antigen receptor complex associate with the protein tyrosine phosphatase, CD45". The Journal of Biological Chemistry. 269 (25): 17238–17244. doi:10.1016/S0021-9258(17)32545-0. PMID 7516335. https://doi.org/10.1016%2FS0021-9258%2817%2932545-0 ↩

  14. Koretzky GA, Kohmetscher M, Ross S (April 1993). "CD45-associated kinase activity requires lck but not T cell receptor expression in the Jurkat T cell line". The Journal of Biological Chemistry. 268 (12): 8958–8964. doi:10.1016/S0021-9258(18)52965-3. PMID 8473339. https://doi.org/10.1016%2FS0021-9258%2818%2952965-3 ↩

  15. Ng DH, Watts JD, Aebersold R, Johnson P (January 1996). "Demonstration of a direct interaction between p56lck and the cytoplasmic domain of CD45 in vitro". The Journal of Biological Chemistry. 271 (3): 1295–1300. doi:10.1074/jbc.271.3.1295. PMID 8576115. https://doi.org/10.1074%2Fjbc.271.3.1295 ↩

  16. Wu L, Fu J, Shen SH (April 2002). "SKAP55 coupled with CD45 positively regulates T-cell receptor-mediated gene transcription". Molecular and Cellular Biology. 22 (8): 2673–2686. doi:10.1128/mcb.22.8.2673-2686.2002. PMC 133720. PMID 11909961. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC133720 ↩

  17. Gabaev I, Steinbrück L, Pokoyski C, Pich A, Stanton RJ, Schwinzer R, et al. (December 2011). "The human cytomegalovirus UL11 protein interacts with the receptor tyrosine phosphatase CD45, resulting in functional paralysis of T cells". PLoS Pathogens. 7 (12): e1002432. doi:10.1371/journal.ppat.1002432. PMC 3234252. PMID 22174689. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234252 ↩

  18. Windheim M, Southcombe JH, Kremmer E, Chaplin L, Urlaub D, Falk CS, et al. (December 2013). "A unique secreted adenovirus E3 protein binds to the leukocyte common antigen CD45 and modulates leukocyte functions". Proceedings of the National Academy of Sciences of the United States of America. 110 (50): E4884 – E4893. doi:10.1073/pnas.1312420110. PMC 3864294. PMID 24218549. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864294 ↩

  19. Mole B (2024-07-15). "Genetic cloaking of healthy cells opens door to universal blood cancer therapy". Ars Technica. Retrieved 2024-07-15. https://arstechnica.com/science/2024/07/genetic-cloaking-of-healthy-cells-opens-door-to-universal-blood-cancer-therapy/ ↩

  20. Mole B (2024-07-15). "Genetic cloaking of healthy cells opens door to universal blood cancer therapy". Ars Technica. Retrieved 2024-07-15. https://arstechnica.com/science/2024/07/genetic-cloaking-of-healthy-cells-opens-door-to-universal-blood-cancer-therapy/ ↩

  21. Mole B (2024-07-15). "Genetic cloaking of healthy cells opens door to universal blood cancer therapy". Ars Technica. Retrieved 2024-07-15. https://arstechnica.com/science/2024/07/genetic-cloaking-of-healthy-cells-opens-door-to-universal-blood-cancer-therapy/ ↩

  22. Mobraaten LE (1994). "JAX NOTES: Ly5 Gene Nomenclature, C57BL/6J and SJL/J - A History of Change". The Jackson Laboratory. Archived from the original on 2015-01-08. Retrieved 2015-01-08. https://web.archive.org/web/20150108142539/http://jaxmice.jax.org/jaxnotes/archive/458b.html ↩

  23. Mercier FE, Sykes DB, Scadden DT (June 2016). "Single Targeted Exon Mutation Creates a True Congenic Mouse for Competitive Hematopoietic Stem Cell Transplantation: The C57BL/6-CD45.1(STEM) Mouse". Stem Cell Reports. 6 (6): 985–992. doi:10.1016/j.stemcr.2016.04.010. PMC 4911492. PMID 27185283. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911492 ↩

  24. "002014 - B6.SJL-Ptprc Pepc/BoyJ". www.jax.org. Retrieved 2020-10-11. https://www.jax.org/strain/002014 ↩