PTPRC and Associated Diseases
Protein tyrosine phosphatase receptor C (PTPRC) is an important transmembrane glycoprotein on the cell surface of immunological and hematological systems. While performing normal cell functions, PTPRC is also used as a cell surface recognition differentiation cluster 45 (CD45) for cell recognition and labeling. With the development of immunotherapies targeting CD45 and advances in molecular biology, the medical and biological significance of CD45 has steadily increased.
Structure of PTPRC
PTPRC is a large glycoprotein composed of four unique domains. The cytoplasmic domain of PTPRC has two tandem PTPase domains, in which the D1 domain is responsible for the activity of enzymatic, while the D2 domain can be phosphorylated by the c-terminal Src kinase. The extramembrane structure of PTPRC molecules forms isoforms through alternative splicing or glycosylation of PTPRC gene exons, and this alternative expression is characterized by the formation of combinations of 0, 1, 2, or 3 exons. A total of six human PTPRC isoforms have been characterized, constituting heterogeneity in the extramembrane structure, participating in the expression of the detected isoforms, and interacting with specific ligands to activate downstream pathways. It is noteworthy that all isoforms exhibit differences in the extracellular domain and have the same enzymatic activity and intracellular structure.
Fig 1. An illustration of PTPRC structure. (Barashdi, 2021)
Function of PTPRC
PTPRC is present in virtually all cells, a property that has led to its designation as CD45 and its use as a diagnostic tool to identify blood-derived cells. PTPRC affects immune function by modulating TCR signaling, cytokine responses, lymphocyte survival, and modulating the activity of T-cell and B-cell antigen receptors. Binding of PTPRC to macrophage galectin produces pro-inflammatory cytokines, leading to apoptosis of T cells. The biological functions and associated diseases of PTPRC are listed below.
| Function | Physiology | Altered PTPRC Consequences |
|
Regulates the activity of SFK Initiates TCR signaling |
T and B- lymphocytes tolerance, activation, development, and survival |
T- and B-cell dysfunction Autoimmune infectious diseases Affects the adhesion and migration of immune cells |
| Regulation of calcium NF- AT TCA pathway | Enhanced cell movement | Reduced insulin receptor signaling, leading to reduced matrix metalloproteinase secretion and defective cell motility |
| Inhibition of pineapple oil-12-myristate-13-acetate-dependent activation and tyrosine phosphorylation of protein kinase C |
Regulates FLT3 signaling in vivo Negative regulation of monocyte differentiation |
Myeloproliferative Neoplasms Acute Myelogenous Leukemia Ectopic Bone Formation |
|
DOK-1 recruitment to the proximal plasma membrane Regulation of cytokine and chemokine production and signaling |
Downstream for JNK and P38 pathway | Severe combined immunodeficiency |
PTPRC in Non-Cancer Diseases
Mutation or functional impairment of PTPRC disrupts the balance of phosphatases and leads to severe immunodeficiency diseases and malignant tumors. C77G and A138G are the two most common mutations in the human PTPRC gene.
The C77G mutation will affect the splicing of exon 4, resulting in the deficiency of CD45RO isoenzyme, which will lead to immune hepatitis, HIV and other immune diseases. The A138G mutation alters the CD45 isoenzyme, increasing the number of memory-activated lymphocytes. People who carry this allele are more likely to have Graves' disease and hepatitis B.
PTPRC in Cancer
The absence or dysfunction of PTPRC is strongly associated with hematological malignancies, a property that allows PTPRC to be used as a diagnostic criterion to distinguish lymphocytes from neoplastic cells in acute lymphoblastic leukemia. During the progression of acute myeloid leukemia, the position of PTPRC on the lipid valve changes, thereby affecting the dephosphorylation of SFKs and the proliferation ability of leukemia cells. Interaction between galectin-1 and PTPRC carbohydrates sensitizes lymphoma cells to apoptosis in diffuse large B-cell lymphoma.
Fig 2. Recognition of lymphocyte subsets in peripheral blood leukocytes using CD45 as a surface antigen. (Mijeong, 2011)
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References
- Barashdi, M.A.A.; et al. Protein tyrosine phosphatase receptor type C (PTPRC or CD45). Molecules in pathogenesis. 2021, 74: 548-552.
- Mijeong, M.D.; et al. Comparative quantitative analysis of cluster of differentiation 45 antigen expression on lymphocyte subsets. The Korean Society for Laboratory Medicine. 2011, 31: 148-153.
