 | This article may be too technical for most readers to understand.(July 2024) |
Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRC gene. [5] PTPRC is also known as CD45 antigen (CD stands for cluster of differentiation), which was originally called leukocyte common antigen (LCA). [6]
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.[ citation needed ]
CD45 is a type I transmembrane protein that is present in various isoforms on all differentiated hematopoietic cells (except erythrocytes and plasma cells). [7] 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.[ citation needed ]
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. [8]
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. [9]
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. [ citation needed ]
CD45 isoforms show cell-type and differentiation-stage specific expression, a pattern which is quite well conserved in mammals. [10] 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.[ citation needed ]
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).
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. [18] 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. [19]
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.[ citation needed ]
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. [20] 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. [20]
There are two identifiable alleles of CD45 in mice: CD45.1 (Ly5.1 historically) and CD45.2 (Ly5.2 historically). [21] 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.[ citation needed ]
In 2016 a new knock-in mouse was generated on the C57BL/6 background to be a perfect congenic strain. [22] 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. [23]
Complement receptor type 1 (CR1) also known as C3b/C4b receptor or CD35 is a protein that in humans is encoded by the CR1 gene.
Tyrosin-protein kinase Lck is a 56 kDa protein that is found inside lymphocytes and encoded in the human by the LCK gene. The Lck is a member of Src kinase family (SFK) and is important for the activation of T-cell receptor (TCR) signaling in both naive T cells and effector T cells. The role of Lck is less prominent in the activation or in the maintenance of memory CD8 T cells in comparison to CD4 T cells. In addition, the constitutive activity of the mouse Lck homolog varies among memory T cell subsets. It seems that in mice, in the effector memory T cell (TEM) population, more than 50% of Lck is present in a constitutively active conformation, whereas less than 20% of Lck is present as active form in central memory T cells. These differences are due to differential regulation by SH2 domain–containing phosphatase-1 (Shp-1) and C-terminal Src kinase.
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.
CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that prevents the overactivation of the immune system and the development of autoimmune diseases.
Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the PTPN6 gene.
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a cytoplasmatic protein encoded by gene PTPN22 and a member of PEST family of protein tyrosine phosphatases. This protein is also called "PEST-domain Enriched Phosphatase" ("PEP") or "Lymphoid phosphatase" ("LYP"). The name LYP is used strictly for the human protein encoded by PTPN22, but the name PEP is used only for its mouse homolog. However, both proteins have similar biological functions and show 70% identity in amino acid sequence. PTPN22 functions as a negative regulator of T cell receptor (TCR) signaling, which maintains homeostasis of T cell compartment.
Receptor-type tyrosine-protein phosphatase alpha is an enzyme that in humans is encoded by the PTPRA gene.
Receptor-type tyrosine-protein phosphatase F is an enzyme that, in humans, is encoded by the PTPRF gene.
CD244 also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene.
Signaling lymphocytic activation molecule 1 is a protein that in humans is encoded by the SLAMF1 gene. Recently SLAMF1 has also been designated CD150.
Leukocyte-associated immunoglobulin-like receptor 1 is a protein that in humans is encoded by the LAIR1 gene. LAIR1 has also been designated as CD305.
Protein tyrosine phosphatase non-receptor type 7 is an enzyme that in humans is encoded by the PTPN7 gene.
Leukocyte immunoglobulin-like receptor subfamily B member 4 is a protein that in humans is encoded by the LILRB4 gene.
Receptor-type tyrosine-protein phosphatase delta is an enzyme that, in humans, is encoded by the PTPRD gene.
Leukocyte receptor tyrosine kinase is an enzyme that in humans is encoded by the LTK gene.
Protein tyrosine phosphatase receptor type C-associated protein is an enzyme that in humans is encoded by the PTPRCAP gene.
Cluster of differentiation CD79A also known as B-cell antigen receptor complex-associated protein alpha chain and MB-1 membrane glycoprotein, is a protein that in humans is encoded by the CD79A gene.
CD79b molecule, immunoglobulin-associated beta, also known as CD79B, is a human gene.
Heterogeneous nuclear ribonucleoprotein L-like is a protein that in humans is encoded by the HNRNPLL gene.
Non-catalytic tyrosine-phosphorylated receptors (NTRs), also called immunoreceptors or Src-family kinase-dependent receptors, are a group of cell surface receptors expressed by leukocytes that are important for cell migration and the recognition of abnormal cells or structures and the initiation of an immune response. These transmembrane receptors are not grouped into the NTR family based on sequence homology, but because they share a conserved signalling pathway utilizing the same signalling motifs. A signaling cascade is initiated when the receptors bind their respective ligand resulting in cell activation. For that tyrosine residues in the cytoplasmic tail of the receptors have to be phosphorylated, hence the receptors are referred to as tyrosine-phosphorylated receptors. They are called non-catalytic receptors, as the receptors have no intrinsic tyrosine kinase activity and cannot phosphorylate their own tyrosine residues. Phosphorylation is mediated by additionally recruited kinases. A prominent member of this receptor family is the T-cell receptor.
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