Ly6

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Ly6 also known as lymphocyte antigen 6 or urokinase-type plasminogen activator receptor (uPAR) is family of proteins that share a common structure but differ in their tissue expression patterns and function. Ly6 are cysteine-rich proteins that form disulfide bridges and contain a LU domain. These proteins are GPI-anchored to the cell membrane or are secreted. A total of 35 human and 61 mouse Ly6 family members have been identified. [1] Depending on which tissues they are expressed in, LY6 family members have different roles. They are expressed in various types of tissues and their expression dependent on the stage of cell differentiation. [1] [2] For example, they are involved in cell proliferation, cell migration, cell–cell interactions, immune cell maturation, macrophage activation, and cytokine production. [3] [1] Their overexpression or dysregulation, for example due to point mutations, is associated with tumorogenesis and autoimmune diseases. [4] [5] This family was discovered in the 1970s, [6] and these proteins are still used as markers of distinct stage of leukocyte differentiation. [3]

Contents

Gene organization

Genes encoding human Ly6 family members are located in clusters on chromosomes 6, 8, 11 and 19. In the murine genome family members are located on chromosomes 17, 15, 9 and 7, respectively. [4] [3] [1] Genes encoding Ly6 proteins with one LU domain consist of 3 exons and 2 introns. The first exon encodes the signal peptide, Exons 2 and 3 encode the LU domain, and exon 3 also encodes the GPI anchor. [1]

Protein structure

Ly6 proteins are characterized by the LU domain. Typically, they contain one LU domain, but some members of the family have multiple LU domains. The LU domain consists of 60-80 AA and contains 10 cysteines arranged in a specific pattern that allows the creation of 5 disulfide bridges which in turn allow the formation of a three-fingered (3F) structural motif. [4] [1]

Based on their subcellular localization, these proteins are classified as GPI-anchored to the cell membrane or secreted. [1]

Expression

Although the Ly6 family members share a common structure, their expression varies in different tissues and is regulated depending on the stage of cell differentiation.

Many Ly6 family members are expressed in hematopoietic precursors and differentiated hematopoietic cells in a lineage-specific manner and making them useful cell surface markers for leukocytes, facilitating identification of distinct leukocyte sub-population. [3]

Further, the Ly6 family proteins are also expressed, for example, by sperm, neurons, keratinocytes and epithelial cells. [1]

Function

Ly6 family proteins have different functions depending on expression in different tissues. They play an important role in the immune response to infection and maintaining homeostasis in response to varying environmental conditions. It is involved in cell proliferation, cell migration, cell–cell interactions, immune cell maturation, macrophage activation, and cytokine production. It is also involved in complement activity, neuronal activity, angiogenesis, tumorogenesis and wound healing. [3] [1]

Clinical relevance

Many Ly6 family proteins (with the notable exception of SLURP1) are over-expressed in inflamed tissues and in tumors. They are therefore used as tumor markers and are also potential therapeutic targets. [1] [6] [4]

Some point mutations in Ly6 family proteins are associated with autoimmune diseases, such as psoriasis vulgaris. [4]

Ly6 proteins

Examples of Ly6 proteins include:

Related Research Articles

Urokinase

Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947. Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.

Urokinase receptor

The Urokinase receptor, also known as urokinase plasminogen activator surface receptor (uPAR) or CD87, is a protein encoded in humans by the PLAUR gene. It is a multidomain glycoprotein tethered to the cell membrane with a glycosylphosphotidylinositol (GPI) anchor. uPAR was originally identified as a saturable binding site for urokinase on the cell surface.

ICAM-1

ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.

L-selectin

L-selectin, also known as CD62L, is a cell adhesion molecule found on leukocytes and the preimplantation embryo. It belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups. It is cleaved by ADAM17.

Integrin alpha L

Integrin, alpha L , also known as ITGAL, is a protein that in human is encoded by ITGAL gene. CD11a functions in the immune system. It is involved in cellular adhesion and costimulatory signaling. It is the target of the drug efalizumab.

PTPRC

Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRC gene. PTPRC is also known as CD45 antigen, which was originally called leukocyte common antigen (LCA).

CD90

Thy-1 or CD90 is a 25–37 kDa heavily N-glycosylated, glycophosphatidylinositol (GPI) anchored conserved cell surface protein with a single V-like immunoglobulin domain, originally discovered as a thymocyte antigen. Thy-1 can be used as a marker for a variety of stem cells and for the axonal processes of mature neurons. Structural study of Thy-1 led to the foundation of the Immunoglobulin superfamily, of which it is the smallest member, and led to some of the initial biochemical description and characterization of a vertebrate GPI anchor and also the first demonstration of tissue specific differential glycosylation.

CD69

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

HLA-F

HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene.

HLA-DMB

HLA class II histocompatibility antigen, DM beta chain is a protein that in humans is encoded by the HLA-DMB gene.

CD48

CD48 antigen also known as B-lymphocyte activation marker (BLAST-1) or signaling lymphocytic activation molecule 2 (SLAMF2) is a protein that in humans is encoded by the CD48 gene.

LSP1

Lymphocyte-specific protein 1 is a protein that in humans is encoded by the LSP1 gene.

CD84

CD84 is a human protein encoded by the CD84 gene.

CD276

Cluster of Differentiation 276 (CD276) or B7 Homolog 3 (B7-H3) is a human protein encoded by the CD276 gene.

SLURP1

Secreted Ly-6/uPAR-related protein 1 is a protein that in humans is encoded by the SLURP1 gene. It exerts anti-inflammatory effects, acts as a tumor suppressor, and antagonizes nicotinic receptors.

LU domain

The LU domain is an evolutionarily conserved protein domain of the three-finger protein superfamily. This domain is found in the extracellular domains of cell-surface receptors and in either GPI-anchored or secreted globular proteins, for example the Ly-6 family, CD59, and Sgp-2.

Lymphocyte antigen 6 complex, locus G6E (pseudogene) is a protein that in humans is encoded by the LY6G6E gene.

Cancer/testis (CT) antigens are a group of proteins united by their importance in development and in cancer immunotherapy. In general, expression of these proteins is restricted to male germ cells in the adult animal. However, in cancer these developmental antigens are often re-expressed and can serve as a locus of immune activation. Thus, they are often classified as tumor antigens. The expression of CT antigens in various malignancies is heterogeneous and often correlates with tumor progression. CT antigens have been described in melanoma, liver cancer, lung cancer, bladder cancer, and pediatric tumors such as neuroblastoma. Gametogenesis offers an important role for many of these antigens in the differentiation, migration, and cell division of primordial germ cells, spermatagonia spermatocytes and spermatids. Because of their tumor-restricted expression and strong in vivo immunogenicity, CT antigens are identified as ideal targets for tumor specific immunotherapeutic approaches and prompted the development of several clinical trials of CT antigens-based vaccine therapy. CT antigens have been found to have at least 70 families so far, including about 140 members, most of which are expressed during spermatogenesis. Their expression are mainly regulated by epigenetic events, specifically, DNA methylation.

Three-finger protein

Three-finger proteins or three-finger protein domains are a protein superfamily consisting of small, roughly 60-80 amino acid residue protein domains with a common tertiary structure: three beta strand loops extended from a hydrophobic core stabilized by disulfide bonds. The family is named for the outstretched "fingers" of the three loops. Members of the family have no enzymatic activity, but are capable of forming protein-protein interactions with high specificity and affinity. The founding members of the family, also the best characterized by structure, are the three-finger toxins found in snake venom, which have a variety of pharmacological effects, most typically by disruption of cholinergic signaling. The family is also represented in non-toxic proteins, which have a wide taxonomic distribution; 3FP domains occur in the extracellular domains of some cell-surface receptors as well as in GPI-anchored and secreted globular proteins, usually involved in signaling.

LYPD6B

LY6/PLAUR Domain Containing 6B, also known under the name Cancer/Testis Antigen 116 (CTA116) and LYPD7 is encoded by the LYPD6B gene. LYPD6B is a member of the lymphocyte antigen 6 (LY6) protein family. It is expressed in the testis, lungs, stomach and the prostate and in the nervous system where it acts as a modulator of nicotinic acetylcholine receptor activity.

References

  1. 1 2 3 4 5 6 7 8 9 10 Loughner CL, Bruford EA, McAndrews MS, Delp EE, Swamynathan S, Swamynathan SK (April 2016). "Organization, evolution and functions of the human and mouse Ly6/uPAR family genes". Human Genomics. 10 (1): 10. doi:10.1186/s40246-016-0074-2. PMC   4839075 . PMID   27098205.
  2. ↑ Lee PY, Wang JX, Parisini E, Dascher CC, Nigrovic PA (October 2013). "Ly6 family proteins in neutrophil biology". Journal of Leukocyte Biology. 94 (4): 585–94. doi:10.1189/jlb.0113014. PMID   23543767. S2CID   1252351.
  3. 1 2 3 4 5 Kong HK, Park JH (November 2012). "Characterization and function of human Ly-6/uPAR molecules". BMB Reports. 45 (11): 595–603. doi:10.5483/bmbrep.2012.45.11.210. PMC   4133805 . PMID   23186997.
  4. 1 2 3 4 5 Upadhyay G (2019). "Emerging Role of Lymphocyte Antigen-6 Family of Genes in Cancer and Immune Cells". Frontiers in Immunology. 10: 819. doi: 10.3389/fimmu.2019.00819 . PMC   6491625 . PMID   31068932.
  5. ↑ Sidenius N, Blasi F (June 2003). "The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy". Cancer and Metastasis Reviews. 22 (2–3): 205–22. doi:10.1023/A:1023099415940. PMID   12784997. S2CID   5765336.
  6. 1 2 McKenzie IF, Gardiner J, Cherry M, Snell GD (March 1977). "Lymphocyte antigens: Ly-4, Ly-6, and Ly-7". Transplantation Proceedings. 9 (1): 667–9. PMID   68598.
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