Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRCgene.[1] PTPRC is also known as CD45antigen (CD stands for cluster of differentiation), which was originally called leukocyte common antigen (LCA).[2]
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]
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, CD45R0, CD45R (ABC).
CD45RA is located on naive T cells and CD45R0 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, CD45R0, 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.
CD45 has been recently shown to interact with the HCMV UL11 protein. This interaction results in functional paralysis of T cells.[11] 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.[12]
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.[13]
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).[14] 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.
↑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. ISBN1-84110-100-1.
↑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. PMID9148925.
↑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. PMID10921916.
↑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. PMID11564800.
↑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. PMID7516335.
↑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. PMID8473339.
↑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. PMID8576115.
↑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. A unique secreted adenovirus E3 protein binds to the leukocyte common antigen CD45 and modulates leukocyte functions. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):E4884-93.
Tchilian EZ, Beverley PC (2002). "CD45 in memory and disease". Arch. Immunol. Ther. Exp. (Warsz.). 50 (2): 85–93. PMID12022705.
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:10.3109/10428190309178767. PMID14565647.
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. PMID15057492.
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. PMID15275963.
Jameson R (2006). "CD45". Immunology course for undergraduates. Davidson College. Retrieved 2011-10-24.
