CD13 (aminopeptidase N, membrane alanyl aminopeptidase, APN, EC 3.4.11.2, and ANPEP) is a ubiquitously expressed protease with multiple functions. As an enzyme, CD13 regulates the activity of multiple cytokines by cleaving the N-terminus and participates in antigen processing by trimming peptides bound to MHC class II. Independent of its enzymatic activity, CD13 on the cell membrane also functions through cross-linking-induced signal transduction, regulation of receptor recycling, enhancement of FcγR-mediated phagocytosis, and as a cytokine receptor. CD13 not only regulates the development and activity of immune-related cells but also modulates the function of inflammatory mediators.
CD13 structure:
CD13 is a type II transmembrane, heavily glycosylated metalloproteinase with an extracellular-facing catalytic domain. It is a hippocampal-shaped molecule with seven domains per monomer, a key characteristic of M1 metallopeptidases. It typically forms head-to-head homodimers through hydrophobic interactions. CD13 (sCD13) can also be enzymatically processed into a soluble form that enters the bloodstream for its effects.
(Data source: Mina-Osorio P. Trends Mol Med. 2008)
CD13 signaling pathway and regulation:
Through its enzymatic activity, CD13 participates in the degradation/regulation of numerous bioactive (neuro)peptides, including methyl- and leucine-enkephalins, oxytocin, vasopressin, angiotensin III, and immunomodulatory peptides such as ureatropin. Consequently, CD13 is implicated in blood pressure regulation and nociception, as well as in cell proliferation, migration, invasion, and metastasis, and angiogenesis. In addition to its peptidase activity, many cellular effects can be attributed to non-enzymatic functions of CD13; this is why CD13 is referred to as a moonlighting enzyme.
(Data source: Lendecel U, et al. Biomedicines. 2023)
The non-enzymatic functions of CD13 include activation of signal transduction pathways after binding of CD13 ligand, its role as a receptor mediator for human coronaviruses, human transmissible gastroenteritis virus (TGEV), and cytomegalovirus (HCMV), as well as cell-cell or cell-matrix adhesion, cell trafficking, endothelial invasion, and maintenance of satellite stem cell populations.
(Data source: Lu C, et al. J Immunol. 2020)
Clinical value of CD13:
Marker: CD13 is strongly expressed in cells of the myelomonocytic lineage and is therefore used as a routine marker for the diagnosis of lymphoma/leukemia. It is also a specific surface marker for cancer stem cells such as hepatocellular carcinoma and cholangiocarcinoma.
(Data source: The Human Protein Atlas)
Potential therapeutic targets: CD13 acts through enzyme-dependent and enzyme-independent mechanisms. It can not only regulate the development and activity of immune-related cells, but also regulate the function of inflammatory mediators. It plays an important role in various inflammatory diseases and may be a potential therapeutic target for inflammatory diseases.
Tumor Migration Inhibition: CD13 is involved in multiple biological processes, including cell survival, tumor cell invasion, metastasis, angiogenesis, anticancer drug resistance, and cancer recurrence. Inhibiting the enzymatic activity of CD13 has been shown to inhibit cell migration and/or invasion in a variety of tumors. The development of CD13 inhibitors, including antibodies, peptides, and small molecules, may be a promising therapeutic approach for treating cancer.
