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IL2RA

Official Full Name
interleukin 2 receptor subunit alpha
Organism
Homo sapiens
GeneID
3559
Background
The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-affinity IL2 receptor. Homodimeric alpha chains (IL2RA) result in low-affinity receptor, while homodimeric beta (IL2RB) chains produce a medium-affinity receptor. Normally an integral-membrane protein, soluble IL2RA has been isolated and determined to result from extracellular proteolyisis. Alternately-spliced IL2RA mRNAs have been isolated, but the significance of each is presently unknown. Mutations in this gene are associated with interleukin 2 receptor alpha deficiency. Patients with severe Coronavirus Disease 2019 (COVID-19), the disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have significantly elevated levels of IL2R in their plasma. Similarly, serum IL-2R levels are found to be elevated in patients with different types of carcinomas. Certain IL2RA and IL2RB gene polymorphisms have been associated with lung cancer risk. [provided by RefSeq, Jul 2020]
Synonyms
p55; CD25; IL2R; IMD41; TCGFR; IDDM10;
Bio Chemical Class
Cytokine receptor
Protein Sequence
MDSYLLMWGLLTFIMVPGCQAELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYMLCTGNSSHSSWDNQCQCTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCREPPPWENEATERIYHFVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGEEKPQASPEGRPESETSCLVTTTDFQIQTEMAATMETSIFTTEYQVAVAGCVFLLISVLLLSGLTWQRRQRKSRRTI
Open
Disease
Diabetes mellitus, Hodgkin lymphoma, Human immunodeficiency virus disease, Mature B-cell leukaemia, Solid tumour/cancer, Transplant rejection
Approved Drug
1 +
Clinical Trial Drug
5 +
Discontinued Drug
1 +

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Detailed Information

The interleukin-2 receptor alpha (IL2RA) is a key component in immune signaling, essential for the regulation of immune responses. It plays a central role in the activation of immune cells, such as T cells, and is crucial in controlling immune tolerance. The receptor, composed of three distinct subunits—IL2RA (α), IL2RB (β), and IL2RG (γ)—forms the high-affinity receptor complex. However, homodimeric forms of the IL2RA and IL2RB subunits can result in low- or medium-affinity receptors, respectively. This complex is involved in numerous immune functions, including immune cell proliferation, differentiation, and survival. Its activation also impacts several diseases, including cancers and autoimmune disorders.

The Structure and Function of IL-2 Receptor Alpha

Of the three key components forming the interleukin-2 (IL-2) receptor, IL2RA is the most significant. Mostly on immune cells like T cells and B cells, the receptor helps immunological signals reach the appropriate locations. A major component in regulating immune responses is IL-2RA, often known as CD25, as it facilitates IL-2 binding to its receptor. Starting a sequence of communication activities that activate defense cells depends on this process rather much.

The receptor complex activates once IL-2RA binds to IL-2. The IL-2 receptor consists of three components: IL-2RA, IL-2RB, and IL-2RG. The α-chain (IL-2RA) increases the appeal of the receptor to the cytokine by helping IL-2 bind. For both signaling and binding cytokines, the β-chain (IL-2RB), which is predominantly present in natural killer (NK) cells and other immune cells, is quite crucial. Part of the immune response as a whole, the γ-chain (IL-2RG) helps assemble the receptor complex.

Usually part of the cell membrane, IL-2RA may be separated from the cell surface by external proteolysis, hence creating a version of IL-2RA that can be dissolved in water (sIL-2RA). People with various kinds of cancer and immunological diseases have been reported to have this soluble form in their blood. Some have proposed using this form as a gauge to indicate how active the disease is and how it is developing.

IL-2RA Signaling Pathways

Upon binding to IL-2, the IL-2 receptor activates several critical signaling pathways that regulate immune cell function. One of the most well-studied pathways is the JAK/STAT pathway. This pathway plays a significant role in the development and functional maturation of T and B lymphocytes. Activation of the receptor triggers the recruitment and activation of Janus kinases (JAK1 and JAK3), which phosphorylate key tyrosine residues on the receptor subunits. This allows the recruitment of signal transducer and activator of transcription (STAT) proteins, including STAT1, STAT3, and STAT5. These phosphorylated STAT proteins then form dimers and tetramers that translocate to the nucleus, where they regulate the expression of target genes involved in immune cell activation, proliferation, and differentiation.

Figure 1 illustrates the major IL-2 signaling pathways, including the activation of PI 3-K-AKT, JAK-STAT, and SHC-RAS-MAPK pathways, and potential therapeutic control points for IL-2 signaling.Figure 1. Schematic of Major IL-2 Signaling Pathways. (Liao W, et al., 2013)

In addition to the JAK/STAT pathway, IL-2RA activation also stimulates two other crucial signaling cascades: the mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase (PI3K) pathway. The MAPK pathway is involved in regulating cell proliferation and differentiation, while the PI3K pathway plays an essential role in cell survival and the proliferation and differentiation of lymphocytes. Together, these signaling pathways orchestrate a variety of immune responses that are essential for maintaining immune homeostasis.

IL-2RA in Cancer and Autoimmune Diseases

IL-2RA has also been linked to the worsening of other diseases, like inflammatory disorders and cancer. People with several forms of cancer, including lung cancer, prostate cancer, and colon cancer, have been found to have higher amounts of soluble IL-2RA (sIL-2RA) in their plasma. Often linked with a worse prognosis, elevated levels of sIL-2RA suggest its possible use in cancer diagnosis and tracking.

The immune system in the tumor microenvironment (TME) is very dependent on IL-2 and its receptor complex. Occasionally, IL-2RA could encourage the proliferation of regulatory T cells (Tregs) by IL-2 transmission, hence impairing the capacity of the immune system to fight malignancies and support their proliferation. On the other hand, IL-2 signaling can improve the activity of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, which is more vital for the destruction of tumor cells. The equilibrium between these two conflicting effects of IL-2 signaling in the TME greatly influences how cancer grows and how well anti-cancer treatments work.

Soluble IL-2 Receptor (sIL-2R) and Cancer Therapy

The soluble form of IL-2RA (sIL-2R) has garnered attention as both a biomarker and a potential therapeutic target in cancer treatment. As both a sign and a potential therapeutic target for cancer treatment, individuals are drawn to the soluble version of IL-2RA (sIL-2R). Proteases chop the membrane-bound IL-2 receptor complex, generating sIL-2R. People with several different cancers have it in their blood. It has a longer half-life than the one attached to the membrane and works with IL-2 in a different manner. Hodgkin lymphoma and non-lymphoid malignancies are among tumors that have been shown to have greater levels of sIL-2R. This implies it can be a way to forecast how well a malignancy would do.

Early clinical trials have investigated sIL-2R's potential therapeutic application. Research suggests sIL-2R might kill tumor cells, prevent the formation of new blood vessels into the tumor, and disrupt pathways supporting tumor growth. Targeting IL-2RA directly might also kill cancer cells and disrupt the JAK-STAT signaling pathway, which is crucial for cancer development.

Measuring disease activity in autoimmune disorders such as type 1 diabetes and immunodeficiencies has been made possible by sIL-2R and IL-2RA, which have shown promise as biomarkers. They might potentially work as drugs. Monitoring sIL-2R levels helps physicians choose how to treat patients and track illness progression, hence providing vital information for clinic choices.

References:

  1. Muhammad S, Fan T, Hai Y, et al. Reigniting hope in cancer treatment: the promise and pitfalls of IL-2 and IL-2R targeting strategies. Mol Cancer. 2023;22(1):121.
  2. Chistiakov DA, Voronova NV, Chistiakov PA. The crucial role of IL-2/IL-2RA-mediated immune regulation in the pathogenesis of type 1 diabetes, an evidence coming from genetic and animal model studies. Immunol Lett. 2008;118(1):1-5.
  3. Ahsan N. Induction immunotherapy with IL-2Ra monoclonal antibody in kidney transplantation. Minerva Urol Nefrol. 2003;55(1):67-79.
  4. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38(1):13-25.
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