Tyro3, a member of the TAM (Tyro3, Axl and MerTK) family of receptor tyrosine kinases, has ligands Gas6 and Protein S. It plays crucial roles in multiple biological processes. In macrophages, it skews polarization towards a pro-tumor M2-like phenotype and promotes apoptotic cell clearance (efferocytosis) [1,3]. In the context of cancer, it is overexpressed in many cancer types and functions in promoting tumor cell survival, proliferation, metastasis, and resistance to chemotherapy [6].

In kidney-related studies, genetic ablation of tyro3 in zebrafish recapitulated a nephrotic syndrome phenotype [2]. In mouse models, the knockout of PS (which activates Tyro3) or Tyro3 exacerbates podocyte loss and glomerular disease, while overexpression of PS and Tyro3 attenuates the injury in mice with diabetic kidney disease (DKD) and focal segmental glomerulosclerosis (FSGS) [5]. Also, a TYRO3 agonist (compound C-10) attenuated proteinuria, glomerular injury, and podocyte loss in mouse models of Adriamycin-induced nephropathy and a db/db model of type 2 diabetes, and these effects were lost in Tyro3-knockout mice [4]. In cancer, TYRO3 knockdown suppressed the growth of myeloid leukaemia cell lines, suppressed phosphorylation of downstream molecules, and the expression of survivin and cyclin D1 [7].

In conclusion, Tyro3 is significant in macrophage polarization, apoptotic cell clearance, and tumor-promoting processes in cancer. In kidney diseases, it plays a protective role in podocytes, as demonstrated by gene knockout and overexpression models in mice. These findings highlight its potential as a therapeutic target in both cancer and glomerular diseases.

References:

1. Myers, Kayla V, Amend, Sarah R, Pienta, Kenneth J. 2019. Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment. In Molecular cancer, 18, 94. doi:10.1186/s12943-019-1022-2. https://pubmed.ncbi.nlm.nih.gov/31088471/

2. Zhang, Liwen, Jiang, Song, Shi, Jinsong, Qin, Weisong, Chen, Zhaohong. 2023. TYRO3 protects podocyte via JNK/c-jun-P53 pathway. In Archives of biochemistry and biophysics, 739, 109578. doi:10.1016/j.abb.2023.109578. https://pubmed.ncbi.nlm.nih.gov/36948351/

3. Zhou, Liwen, Matsushima, Glenn K. 2021. Tyro3, Axl, Mertk receptor-mediated efferocytosis and immune regulation in the tumor environment. In International review of cell and molecular biology, 361, 165-210. doi:10.1016/bs.ircmb.2021.02.002. https://pubmed.ncbi.nlm.nih.gov/34074493/

4. Zhong, Fang, Cai, Hong, Fu, Jia, Lee, Kyung, He, John Cijiang. 2023. TYRO3 agonist as therapy for glomerular disease. In JCI insight, 8, . doi:10.1172/jci.insight.165207. https://pubmed.ncbi.nlm.nih.gov/36454644/

5. Min, Lulin, Chen, Yixin, Zhong, Fang, Lee, Kyung, He, John Cijiang. 2024. Role and Mechanisms of Tyro3 in Podocyte Biology and Glomerular Disease. In Kidney diseases (Basel, Switzerland), 10, 398-406. doi:10.1159/000540452. https://pubmed.ncbi.nlm.nih.gov/39430290/

6. Smart, Sherri K, Vasileiadi, Eleana, Wang, Xiaodong, DeRyckere, Deborah, Graham, Douglas K. 2018. The Emerging Role of TYRO3 as a Therapeutic Target in Cancer. In Cancers, 10, . doi:10.3390/cancers10120474. https://pubmed.ncbi.nlm.nih.gov/30501104/

7. Saito, Tatsuya, Itoh, Mai, Tohda, Shuji. . TYRO3 Knockdown Suppresses the Growth of Myeloid Leukaemia Cells. In Anticancer research, 42, 1757-1761. doi:10.21873/anticanres.15652. https://pubmed.ncbi.nlm.nih.gov/35346994/