# KLRK1

## Overview
The KLRK1 gene encodes the NKG2D protein, a type II transmembrane receptor that plays a pivotal role in the immune system. This receptor is primarily expressed on natural killer (NK) cells and CD8+ T cells, where it functions as an activating receptor involved in immune surveillance. The NKG2D receptor is characterized by its C-type lectin-like extracellular domain, which facilitates the recognition of stress-inducible ligands on infected or malignant cells, thereby triggering cytotoxic responses and cytokine production (Gupta2012NKG2D; Lanier2015NKG2D). The receptor's interaction with adaptor proteins, such as DAP10 and DAP12, is crucial for signal transduction and the subsequent activation of immune responses (Wilton2019NKG2D–DAP10). The KLRK1 gene's expression and function have significant clinical implications, particularly in cancer and infectious diseases, where alterations in NKG2D activity can influence disease progression and therapeutic outcomes (Hussein2021Impact; Wang2021Carbon).

## Structure
The KLRK1 gene encodes the NKG2D protein, a type II transmembrane glycoprotein with a C-type lectin-like extracellular domain. This domain is involved in calcium binding and is crucial for ligand interaction (Gupta2012NKG2D; Lanier2015NKG2D). The protein forms a disulfide-linked homodimer, which is essential for its function and stability (Carapito2015Genetics). The NKG2D receptor associates with adaptor proteins DAP10 and DAP12, forming a hexameric complex that is critical for signal transduction (Gupta2012NKG2D; Lanier2015NKG2D).

In humans, alternative splicing of the KLRK1 gene can produce a truncated isoform of NKG2D that lacks the extracellular domain but retains the transmembrane domain, potentially affecting receptor function by sequestering DAP10 (Lanier2015NKG2D). The protein is highly conserved across mammals, with limited polymorphism, and only two alleles differing by a single amino acid (Lanier2015NKG2D). Post-translational modifications, such as glycosylation, play a role in ligand binding and protein stability (Gupta2012NKG2D). The receptor's ligand-binding site is highly degenerate, allowing it to accommodate multiple ligand variations through an 'induced-fit' mechanism (Gupta2012NKG2D).

## Function
The KLRK1 gene encodes the NKG2D receptor, a type II transmembrane glycoprotein with an extracellular C-type lectin domain, primarily expressed on natural killer (NK) cells, CD8+ T cells, and subsets of other T cells (Carapito2015Genetics). In healthy human cells, NKG2D is constitutively expressed on almost all resting CD8+ T cells and NK cells, where it associates with the DAP10 adapter protein to transmit activating signals (Lanier2015NKG2D). This receptor plays a crucial role in immune surveillance by recognizing stress-inducible ligands, such as MICA and MICB, on infected or malignant cells, leading to the activation of cytotoxic responses and cytokine production (Carapito2015Genetics; Bauer1999Activation).

NKG2D functions as both a co-stimulatory and primary recognition receptor, depending on the cell type. In NK cells, it acts as a primary recognition receptor, triggering cytokine release and cytotoxic responses, while in CD8+ T cells, it amplifies TCR-mediated activation (Raulet2003Roles). The receptor's signaling is mediated through adaptor proteins DAP10 and DAP12, which are involved in NK cell survival, cytotoxicity, and cytokine release (Zafirova2011Regulation). The expression of NKG2D ligands is tightly regulated to prevent inappropriate immune activation, ensuring that the receptor's primary function in healthy cells is to maintain readiness for immune response rather than active engagement (Lanier2015NKG2D).

## Clinical Significance
Alterations in the expression or function of the KLRK1 gene, which encodes the NKG2D receptor, have significant clinical implications in various diseases. In non-small cell lung cancer (NSCLC), carbon ion irradiation has been shown to upregulate KLRK1 expression, enhancing NK cell activity and infiltration in tumors. This upregulation is associated with improved prognosis, suggesting a potential therapeutic strategy that combines radiation with NK cell-based therapies to improve outcomes in solid tumors (Wang2021Carbon).

In acute myeloid leukemia (AML), genetic variations in the KLRK1 gene, specifically the presence of the G allele of the rs1049174 SNP, are linked to higher NKG2D expression and favorable clinical outcomes. This suggests that genetic profiling of KLRK1 could be important in predicting patient response to immunotherapy (Hussein2021Impact).

The KLRK1 gene also plays a role in susceptibility to HPV-related cancers. A polymorphism in the NKG2D gene, rs1049174, affects receptor expression and function. The LNK allele is associated with lower NKG2D expression and increased susceptibility to HPV-related cancers, while the HNK allele is linked to higher expression and enhanced NK cell cytotoxicity (Espinoza2016A).

## Interactions
The KLRK1 gene encodes the NKG2D receptor, which is an activating receptor expressed on natural killer (NK) cells and CD8+ T cells. In humans, NKG2D interacts with the DAP10 adapter subunit, while in mice, it can also associate with DAP12 due to alternative splicing. The interaction between NKG2D and its adapter proteins is mediated by charged residues within their transmembrane regions. This association is crucial for signal transduction, as DAP12 contains an immunotyrosine-based activation motif (ITAM) that recruits Syk and ZAP70 tyrosine kinases, whereas DAP10 has a YINM motif that recruits a p85 PI3 kinase and Vav-1 signaling complex (Lanier2015NKG2D).

The NKG2D-DAP10 receptor complex forms a hexameric structure, and its assembly is dependent on intracellular magnesium levels. Cytokines can modulate the expression of NKG2D on NK cells and CD8+ T cells by affecting the transcription and post-transcriptional processing of NKG2D and DAP10 (Lanier2015NKG2D).

NKG2D also recruits the Ena/VASP-like (EVL) protein to the cytotoxic synapse through a signaling pathway involving Grb2 and VAV1. This recruitment is essential for the generation of F-actin, which is necessary for NK cell adhesion and cytotoxicity. EVL interacts with other proteins such as WASP and VASP, facilitating their localization to the synapse and promoting actin polymerization (Wilton2019NKG2D–DAP10).


## References


[1. (Gupta2012NKG2D) Rajesh K. Gupta and G. S. Gupta. NKG2D Activating Receptor, pages 667–691. Springer Vienna, 2012. URL: http://dx.doi.org/10.1007/978-3-7091-1065-2_31, doi:10.1007/978-3-7091-1065-2_31. This article has 0 citations.](https://doi.org/10.1007/978-3-7091-1065-2_31)

[2. (Wang2021Carbon) Jiangtao Wang, Ziying Dai, Yandong Miao, Ting Zhao, Jian Gan, Chengpeng Zhao, Juntao Ran, and Quanlin Guan. Carbon ion (12c6+) irradiation induces the expression of klrk1 in lung cancer and optimizes the tumor microenvironment based on the nkg2d/nkg2d-ls pathway. Cancer Letters, 521:178–195, November 2021. URL: http://dx.doi.org/10.1016/j.canlet.2021.09.003, doi:10.1016/j.canlet.2021.09.003. This article has 12 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.canlet.2021.09.003)

[3. (Raulet2003Roles) David H. Raulet. Roles of the nkg2d immunoreceptor and its ligands. Nature Reviews Immunology, 3(10):781–790, October 2003. URL: http://dx.doi.org/10.1038/nri1199, doi:10.1038/nri1199. This article has 1042 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/nri1199)

[4. (Wilton2019NKG2D–DAP10) Katelynn M. Wilton, Brittany L. Overlee, and Daniel D. Billadeau. Nkg2d–dap10 signaling recruits evl to the cytotoxic synapse to generate f-actin and promote nk cell cytotoxicity. Journal of Cell Science, July 2019. URL: http://dx.doi.org/10.1242/jcs.230508, doi:10.1242/jcs.230508. This article has 15 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.230508)

[5. (Lanier2015NKG2D) Lewis L. Lanier. Nkg2d receptor and its ligands in host defense. Cancer Immunology Research, 3(6):575–582, June 2015. URL: http://dx.doi.org/10.1158/2326-6066.CIR-15-0098, doi:10.1158/2326-6066.cir-15-0098. This article has 616 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1158/2326-6066.CIR-15-0098)

[6. (Carapito2015Genetics) Raphael Carapito and Seiamak Bahram. Genetics, genomics, and evolutionary biology of <scp>nkg</scp>2d ligands. Immunological Reviews, 267(1):88–116, August 2015. URL: http://dx.doi.org/10.1111/imr.12328, doi:10.1111/imr.12328. This article has 98 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1111/imr.12328)

[7. (Zafirova2011Regulation) Biljana Zafirova, Felix M. Wensveen, Maja Gulin, and Bojan Polić. Regulation of immune cell function and differentiation by the nkg2d receptor. Cellular and Molecular Life Sciences, 68(21):3519–3529, September 2011. URL: http://dx.doi.org/10.1007/s00018-011-0797-0, doi:10.1007/s00018-011-0797-0. This article has 86 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-011-0797-0)

[8. (Espinoza2016A) J. Luis Espinoza, Viet H. Nguyen, Hiroshi Ichimura, Trang T. T. Pham, Cuong H. Nguyen, Thuc V. Pham, Mahmoud I. Elbadry, Katsuji Yoshioka, Junji Tanaka, Ly Q. Trung, Akiyoshi Takami, and Shinji Nakao. A functional polymorphism in the nkg2d gene modulates nk-cell cytotoxicity and is associated with susceptibility to human papilloma virus-related cancers. Scientific Reports, December 2016. URL: http://dx.doi.org/10.1038/srep39231, doi:10.1038/srep39231. This article has 43 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/srep39231)

[9. (Hussein2021Impact) Brwa Ali Hussein, Alexander Hallner, Lovisa Wennström, Mats Brune, Anna Martner, Kristoffer Hellstrand, Elin Bernson, and Fredrik B. Thorén. Impact of nk cell activating receptor gene variants on receptor expression and outcome of immunotherapy in acute myeloid leukemia. Frontiers in Immunology, December 2021. URL: http://dx.doi.org/10.3389/fimmu.2021.796072, doi:10.3389/fimmu.2021.796072. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2021.796072)

[10. (Bauer1999Activation) Stefan Bauer, Veronika Groh, Jun Wu, Alexander Steinle, Joseph H. Phillips, Lewis L. Lanier, and Thomas Spies. Activation of nk cells and t cells by nkg2d, a receptor for stress-inducible mica. Science, 285(5428):727–729, July 1999. URL: http://dx.doi.org/10.1126/science.285.5428.727, doi:10.1126/science.285.5428.727. This article has 2346 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1126/science.285.5428.727)