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PTPRC

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Template:PBB Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRC gene.[1] PTPRC is also known as CD45 antigen (CD stands for cluster of differentiation), which was originally called leukocyte common antigen (LCA).[2]

Function

The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus belongs to receptor type PTP. This gene is specifically expressed in hematopoietic cells. This PTP has been shown to be an essential regulator of T- and B-cell antigen receptor signaling. It functions through either direct interaction with components of the antigen receptor complexes or by activating various Src family kinases required for the antigen receptor signaling. This PTP also suppresses JAK kinases, and, thus, functions as a negative regulator of cytokine receptor signaling. Four alternatively spliced transcripts variants of this gene, which encode distinct isoforms, have been reported.[2]

It is a type I transmembrane protein that is in various forms present on all differentiated hematopoietic cells, except erythrocytes and plasma cells, that assists in the activation of those cells (a form of co-stimulation). It is expressed in lymphomas, B-cell chronic lymphocytic leukemia, hairy cell leukemia, and acute nonlymphocytic leukemia. A monoclonal antibody to CD45 is used in routine immunohistochemistry to differentiate between histological sections from lymphomas and carcinomas.[3]

Isoforms

The CD45 family consists of multiple members that are all products of a single complex gene. This gene contains 34 exons and three exons of the primary transcripts are alternatively spliced to generate up to eight different mature mRNAs and after translation eight different protein products. These three exons generate the RA, RB and RC isoforms.

Various isoforms of CD45 exist: CD45RA, CD45RB, CD45RC, CD45RAB, CD45RAC, CD45RBC, CD45RO, CD45R (ABC). CD45RA is located on naive T cells and CD45RO is located on memory T cells. CD45 is also highly glycosylated. CD45R 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. B220 expression is not restricted to B cells and can also be expressed on activated T cells, on a subset of dendritic cells and other antigen-presenting cells.

Naive T lymphocytes express large CD45 isoforms and are usually positive for CD45RA. Activated and memory T lymphocytes express the shortest CD45 isoform, CD45RO, which lacks RA, RB, and RC exons. This shortest isoform facilitates T cell activation.

The cytoplasmic domain of CD45 is one of the largest known and it has an intrinsic phosphatase activity that removes an inhibitory phosphate group on a tyrosine kinase called Lck (in T cells) or Lyn/Fyn/Lck (in B cells) and activates it.

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.[11]

Clinical importance

Stem cells of several varieties, including mesenchymal stem cells and hæmatopoietic stem cells are found in the bone marrow. If a clinician wishes to separate the two, the CD45 marker is used to distinguish the two stem cell types, as CD45 is found on all leukocytes.

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).[12] 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. The CD90.1/CD90.2 system is used in the same manner as the CD45.1/CD45.2 system.

References

  1. ^ Kaplan R, Morse B, Huebner K, Croce C, Howk R, Ravera M, Ricca G, Jaye M, Schlessinger J (September 1990). "Cloning of three human tyrosine phosphatases reveals a multigene family of receptor-linked protein-tyrosine-phosphatases expressed in brain". Proc. Natl. Acad. Sci. U.S.A. 87 (18): 7000–4. doi:10.1073/pnas.87.18.7000. PMC 54670. PMID 2169617.
  2. ^ a b "Entrez Gene: PTPRC protein tyrosine phosphatase, receptor type, C".
  3. ^ Leong, Anthony S-Y; Cooper, Kumarason; Leong, F Joel W-M (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. pp. 121–124. ISBN 1-84110-100-1.
  4. ^ 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". J. Biol. Chem. 272 (20): 13117–25. doi:10.1074/jbc.272.20.13117. PMID 9148925.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ 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". J. Biol. Chem. 275 (41): 32071–6. doi:10.1074/jbc.M003088200. PMID 10921916.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ Baldwin TA, Ostergaard HL (October 2001). "Developmentally regulated changes in glucosidase II association with, and carbohydrate content of, the protein tyrosine phosphatase CD45". J. Immunol. 167 (7): 3829–35. doi:10.4049/jimmunol.167.7.3829. PMID 11564800.
  7. ^ 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". J. Biol. Chem. 269 (25): 17238–44. PMID 7516335.
  8. ^ 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". J. Biol. Chem. 268 (12): 8958–64. PMID 8473339.
  9. ^ 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". J. Biol. Chem. 271 (3): 1295–300. doi:10.1074/jbc.271.3.1295. PMID 8576115.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ Wu L, Fu J, Shen SH (April 2002). "SKAP55 coupled with CD45 positively regulates T-cell receptor-mediated gene transcription". Mol. Cell. Biol. 22 (8): 2673–86. doi:10.1128/mcb.22.8.2673-2686.2002. PMC 133720. PMID 11909961.
  11. ^ Gabaev I, Steinbrück L, Pokoyski C, Pich A, Stanton RJ, Schwinzer R, Schulz TF, Jacobs R, Messerle M, Kay-Fedorov PC (December 2011). "The human cytomegalovirus UL11 protein interacts with the receptor tyrosine phosphatase CD45, resulting in functional paralysis of T cells". PLoS Pathog. 7 (12): e1002432. doi:10.1371/journal.ppat.1002432. PMC 3234252. PMID 22174689.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ Mobraaten LE (1994). "JAX NOTES: Ly5 Gene Nomenclature, C57BL/6J and SJL/J - A History of Change". The Jackson Laboratory.

Bibliography

  • Tchilian EZ, Beverley PC (2002). "CD45 in memory and disease". Arch. Immunol. Ther. Exp. (Warsz.). 50 (2): 85–93. PMID 12022705.
  • Ishikawa H, Tsuyama N, Abroun S, Liu S, Li FJ, Otsuyama K, Zheng X, Kawano MM (2004). "Interleukin-6, CD45 and the src-kinases in myeloma cell proliferation". Leuk. Lymphoma. 44 (9): 1477–81. doi:10.1080/1042819031000097339. PMID 14565647.
  • Stanton T, Boxall S, Bennett A, Kaleebu P, Watera C, Whitworth J, French N, Dawes R, Hill AV, Bodmer W, Beverley PC, Tchilian EZ (2004). "CD45 variant alleles: possibly increased frequency of a novel exon 4 CD45 polymorphism in HIV seropositive Ugandans". Immunogenetics. 56 (2): 107–10. doi:10.1007/s00251-004-0668-z. PMID 15057492.
  • Huntington ND, Tarlinton DM (2005). "CD45: direct and indirect government of immune regulation". Immunol. Lett. 94 (3): 167–74. doi:10.1016/j.imlet.2004.05.011. PMID 15275963.
  • Jameson R (2006). "CD45". Immunology course for undergraduates. Davidson College. Retrieved 2011-10-24.
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