Lrig1, or leucine-rich repeats and immunoglobulin-like domains protein 1, is a significant regulator with multiple functions. It primarily acts as an endogenous feedback regulator of receptor tyrosine kinases (RTKs), especially antagonizing the expression and activities of ERBB and other RTKs [2,5,6]. This regulation is crucial for maintaining cellular homeostasis, as it is involved in processes like stem cell quiescence and tumor suppression. Genetic models, such as knockout mouse models, have been instrumental in studying Lrig1's functions.

In T-cell-specific Lrig1-deleted mice, superior antitumor responses were observed due to the expansion of tumor-specific cytotoxic T lymphocytes with enhanced effector function and survival, suggesting Lrig1 as an inhibitory immune checkpoint receptor [1]. In the context of adult neural stem cells, genetic disruption of Lrig1 in vivo led to enhanced proliferation, indicating its role as a regulator of cell cycle re-entry [3]. Lrig1-deficient regulatory T cells showed impaired suppressive function, while adoptive transfer of CD4 + Lrig1 + T cells alleviated autoimmune symptoms in mouse models [4]. In the colon, inducible knockout of Lrig1 showed it restrains proliferation during development [7]. In the kidney, Lrig1 + cells contribute to kidney development and repair in injury models [8]. In adult neural stem cells, Lrig1 knockout led to increased proliferation likely through impaired TGFβ and BMP signaling [9].

In summary, Lrig1 is a pleiotropic regulator involved in stem cell quiescence, tumor suppression, immune regulation, and tissue development and repair. The use of Lrig1 knockout and conditional knockout mouse models has significantly advanced our understanding of its role in cancer immunotherapy, autoimmunity, and tissue-specific physiological processes.

References:

1. Ta, Hieu Minh, Roy, Dia, Zhang, Keman, Chan, Timothy, Wang, Li Lily. 2024. LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses. In Science immunology, 9, eadi7418. doi:10.1126/sciimmunol.adi7418. https://pubmed.ncbi.nlm.nih.gov/38758807/

2. Ji, Yibing, Kumar, Rahul, Gokhale, Abhiram, Li, Qiuhui, Tang, Dean G. 2021. LRIG1, a regulator of stem cell quiescence and a pleiotropic feedback tumor suppressor. In Seminars in cancer biology, 82, 120-133. doi:10.1016/j.semcancer.2020.12.016. https://pubmed.ncbi.nlm.nih.gov/33476721/

3. Marqués-Torrejón, María Ángeles, Williams, Charles A C, Southgate, Benjamin, Parrinello, Simona, Pollard, Steven M. 2021. LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells. In Nature communications, 12, 2594. doi:10.1038/s41467-021-22813-w. https://pubmed.ncbi.nlm.nih.gov/33972529/

4. Moon, Jae-Seung, Ho, Chun-Chang, Park, Jong-Hyun, Seong, Rho Hyun, Lee, Sang-Kyou. 2023. Lrig1-expression confers suppressive function to CD4+ cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis. In Nature communications, 14, 5382. doi:10.1038/s41467-023-40986-4. https://pubmed.ncbi.nlm.nih.gov/37666819/

5. Neirinckx, Virginie, Hedman, Hakan, Niclou, Simone P. 2017. Harnessing LRIG1-mediated inhibition of receptor tyrosine kinases for cancer therapy. In Biochimica et biophysica acta. Reviews on cancer, 1868, 109-116. doi:10.1016/j.bbcan.2017.02.007. https://pubmed.ncbi.nlm.nih.gov/28259645/

6. Wang, Y, Poulin, E J, Coffey, R J. 2013. LRIG1 is a triple threat: ERBB negative regulator, intestinal stem cell marker and tumour suppressor. In British journal of cancer, 108, 1765-70. doi:10.1038/bjc.2013.138. https://pubmed.ncbi.nlm.nih.gov/23558895/

7. Hopton, Rachel E, Jahahn, Nicholas J, Zemper, Anne E. 2023. Lrig1 drives cryptogenesis and restrains proliferation during colon development. In American journal of physiology. Gastrointestinal and liver physiology, 325, G570-G581. doi:10.1152/ajpgi.00094.2023. https://pubmed.ncbi.nlm.nih.gov/37873577/

8. Lee, Yura, Kim, Kwang H, Park, Jihwan, Coffey, Robert J, Nam, Ki Taek. 2024. Regenerative Role of Lrig1+ Cells in Kidney Repair. In Journal of the American Society of Nephrology : JASN, 35, 1702-1714. doi:10.1681/ASN.0000000000000462. https://pubmed.ncbi.nlm.nih.gov/39120954/

9. Ouzikov, Stephanie, Edwards, Kyshona M, Anandampillai, Tanvi, Lee, Jeffrey E, Yuzwa, Scott A. 2024. LRIG1 controls proliferation of adult neural stem cells by facilitating TGFβ and BMP signalling pathways. In Communications biology, 7, 845. doi:10.1038/s42003-024-06524-8. https://pubmed.ncbi.nlm.nih.gov/38987622/