Lrfn2, also known as SALM1 (synaptic adhesion-like molecule), is a synaptic adhesion protein. It can interact with N-methyl-D-aspartate receptors (NMDARs) and scaffold proteins, and is involved in regulating synaptic function, hematopoiesis, and potentially cancer-related processes [3,5,7]. It participates in pathways such as Wnt/β-catenin and NF-κB in cancer contexts, and in the regulation of AMPA receptor trafficking in the nervous system [2,3]. Genetic models like knockout mice are valuable for studying its functions.

In Lrfn2-mutant mice, there are suppressed synaptic plasticity and inhibitory synapse development, along with abnormal social communication and startle response [5]. Lrfn2-knockout mice exhibit autism-like behaviors, enhanced memory formation, and synaptic plasticity, with changes in synaptic proteins and spine morphology [6]. In addition, Lrfn2-deficient mice show abnormalities in erythropoietic systems, including multilineage blood cell changes and altered NMDA receptor-mediated calcium influx in erythroblasts [7]. In bladder cancer, Lrfn2 shapes a non-inflammatory tumor microenvironment, inhibiting CD8+ T-cell infiltration and functional transition, leading to immunotherapy resistance [1]. In esophageal squamous cell carcinoma (ESCC), overexpression of Lrfn2 suppresses tumor progression by regulating the Wnt/β-catenin and NF-κB pathways [3]. Also, the Lrfn2 gene variant rs2494938 is associated with an increased susceptibility to esophageal cancer in certain populations [4,8].

In summary, Lrfn2 plays crucial roles in synaptic function, hematopoiesis, and cancer-related processes. The study of Lrfn2 knockout mouse models has provided insights into its functions in neurological and hematological processes, as well as its implications in cancer, such as in bladder cancer immunotherapy resistance and ESCC progression. This contributes to our understanding of related disease mechanisms and potential therapeutic targets.

References:

1. Yu, Anze, Hu, Jiao, Fu, Liangmin, Zu, Xiongbing, Luo, Junhang. . Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8+ T cell infiltration and functional transition. In Journal for immunotherapy of cancer, 11, . doi:10.1136/jitc-2023-007230. https://pubmed.ncbi.nlm.nih.gov/37802603/

2. McMillan, Kirsty J, Banks, Paul J, Hellel, Francesca Ln, Wilkinson, Kevin A, Cullen, Peter J. 2021. Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2. In eLife, 10, . doi:10.7554/eLife.59432. https://pubmed.ncbi.nlm.nih.gov/34251337/

3. Zhou, Yu, Xu, Lijuan, Wang, Jiru, Wang, Qilong, Gao, Yong. 2022. LRFN2 binding to NMDAR inhibits the progress of ESCC via regulating the Wnt/β-Catenin and NF-κB signaling pathway. In Cancer science, 113, 3566-3578. doi:10.1111/cas.15510. https://pubmed.ncbi.nlm.nih.gov/35879265/

4. Shah, Ruchi, Sharma, Varun, Singh, Hemender, Dar, Nazir Ahmed, Sharma, Swarkar. . LRFN2 gene variant rs2494938 provides susceptibility to esophageal cancer in the population of Jammu and Kashmir. In Journal of cancer research and therapeutics, 16, S156-S159. doi:10.4103/jcrt.JCRT_613_19. https://pubmed.ncbi.nlm.nih.gov/32880595/

5. Li, Yan, Kim, Ryunhee, Cho, Yi Sul, Bae, Yong-Chul, Kim, Eunjoon. 2018. Lrfn2-Mutant Mice Display Suppressed Synaptic Plasticity and Inhibitory Synapse Development and Abnormal Social Communication and Startle Response. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 38, 5872-5887. doi:10.1523/JNEUROSCI.3321-17.2018. https://pubmed.ncbi.nlm.nih.gov/29798891/

6. Morimura, Naoko, Yasuda, Hiroki, Yamaguchi, Kazuhiko, Yoshikawa, Takeo, Aruga, Jun. 2017. Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice. In Nature communications, 8, 15800. doi:10.1038/ncomms15800. https://pubmed.ncbi.nlm.nih.gov/28604739/

7. Maekawa, Ryuta, Muto, Hideki, Hatayama, Minoru, Aruga, Jun. 2021. Dysregulation of erythropoiesis and altered erythroblastic NMDA receptor-mediated calcium influx in Lrfn2-deficient mice. In PloS one, 16, e0245624. doi:10.1371/journal.pone.0245624. https://pubmed.ncbi.nlm.nih.gov/33481887/

8. Wang, Jiru, Wang, Qiuzi, Wei, Bin, Gao, Yong, Chen, Xiaofei. 2019. Intronic polymorphisms in genes LRFN2 (rs2494938) and DNAH11 (rs2285947) are prognostic indicators of esophageal squamous cell carcinoma. In BMC medical genetics, 20, 72. doi:10.1186/s12881-019-0796-9. https://pubmed.ncbi.nlm.nih.gov/31053115/