CD74, also known as the invariant chain or Ii, is a non-polymorphic glycoprotein is a transmembrane glycoprotein. CD74 molecule is a cell membrane high-affinity receptor for macrophage migration inhibitory factor (MIF) and D dopachrome tautomerase (D-DT/MIF-2). In mice, two isoforms of the protein exist due to alternative splicing, which is referred to p31 and p41, respectively. The Human CD74 molecule has 29-46 NH2-terminal intracytoplasmic residues, a 26-aa hydrophobic transmembrane region, and a 160-aa extracytoplasmic domain containing two N-linked carbohydrate chains. The most common isoform is 33 kDa (p33), but there are also p35, p41, and p43 isoforms in humans.
Fig.1 Structure of the different murine and human CD74 isoforms. (Schroder, 2016)
CD74 interacts with MHC class I and II proteins, contributing to antigen presentation. CD74 directs transport of MHC class II α and β chains from the endoplasmic reticulum or the cell surface to endosomes. In addition, CD74 blocks the peptide-binding cleft of class II MHC and prevents premature binding of antigenic peptides. In endosomes, proteases degrade CD74, releasing MHC class II molecules. Prevention of CD74 degradation promotes the cell surface localization of MHC II.
Fig.2 The role of CD74 in the MHCII antigen presentation pathway. (Schroder, 2016)
Cell surface CD74 is a receptor for MIF and MIF-2. However, the binding of MIF to CD74 is not sufficient to trigger intracellular signal transduction because CD74 lacks signaling motifs. MIF signaling via CD74 depends on the presence of the co-receptor proteins CD44 or CXCR4 which are able to recruit signaling components with their cytoplasmic domains. These include a transient and sustained activation of the extracellular signal-regulated kinase (ERK)-1/2 MAP kinase as well as of the phosphoinositide-3-kinase (PI3K)/AKT pathways. In B cells, MIF binding to CD74 led to AKT, Syk and NF-kB activation, and proliferation in a CD44-dependant manner.
Fig.3 Signal transduction pathways emanating from MIF-bound CD74-CD44 complexes. (Lindner, 2017)
In relation to its physiological expression pattern, CD74 has also been detected in a number of hematological malignancies like multiple myeloma. In addition, in a wide spectrum of neoplasms, which are not of myeloid or lymphatic origin, CD74 expression has been observed. These include cancers of the breast, the gastrointestinal tract, the lung, the kidney, the bladder, the prostate, the pancreas and the central nervous system. CD74 has a strong link to carcinogenesis, as does MIF. MIF binding to CD74 might contribute to carcinogenesis in chronic conditions through the upregulation of proinflammatory cytokines, including Interleukin-8 (IL-8), which up-regulates CD74 and has its own mechanisms leading to increased proliferation, tumor growth and angiogenesis.
CD74 is expressed in antigen-presenting cells (APCs), as well as epithelial cells. CD74 can significantly influence and modulate signal transduction, endocytic membrane trafficking and cell migration in APCs. In addition, CD74 is highly expressed in inflammatory disorders and cancers. Its roles as an accessory signal receptor on the cell surface and the ability to interact with other signaling molecules make CD74 an attractive therapeutic target and a putative predictive marker for the treatment of cancer.
Responding to customer needs, Creative Biolabs has expanded its tumor marker assay services. Our portfolio of systems and assay can help support the essential role of your research. Our CD74 assay portfolio services for research include but are not limited to:
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