Scyl3, or SCY1-like pseudokinase 3, belongs to the SCY1-like (SCYL) family of protein kinases. Members of this family are evolutionarily conserved, ubiquitously expressed, and characterized by an N-terminal pseudokinase domain. They are thought to be involved in regulating essential cellular processes such as intracellular trafficking and may play a role in maintaining motor neuron viability [2,3].

In a study on hepatocellular carcinoma (HCC), SCYL3 was found to be often overexpressed, especially in metastatic tumors, and was associated with worse patient survival. Suppression of SCYL3 in HCC cells attenuated cell proliferation, migration, and in vivo metastasis, while its overexpression increased tumor development and metastasis in Tp53 KO/c-Myc OE mice. Mechanistically, SCYL3 physically binds and regulates the stability and transactivating activity of ROCK2, leading to increased formation of actin stress fibers and focal adhesions, thus promoting HCC progression [1].

In motor neuron-related research, although lack of Scyl3 in mice had no apparent effect on embryogenesis and postnatal life, it accelerated the onset of the motor neuron disorder caused by Scyl1 deficiency. Scyl1/Scyl3 double-deficient mice showed earlier-onset growth abnormalities, motor dysfunction, and other symptoms similar to amyotrophic lateral sclerosis, suggesting that SCYL1 and SCYL3 work together to maintain motor neuron viability and regulate TDP-43 proteostasis [2].

In conclusion, Scyl3 plays a crucial role in promoting the progression of HCC and in maintaining motor neuron viability. The gene knockout and related mouse models have been instrumental in revealing its functions in these disease-related biological processes, providing insights into potential therapeutic strategies for HCC and understanding the mechanisms underlying motor neuron diseases.