Phactr4, short for phosphatase and actin regulator 4, is a member of the Phactr family of protein phosphatase 1 (PP1)- and actin-binding proteins. It plays a role in various biological processes such as regulating cytoskeletal dynamics, cell-cycle progression, and integrin signaling. It is involved in pathways like RHO/ROCK, NF-κB/NLRP3, and IL-6/Stat3, and is important for normal development and tissue homeostasis [2,3,4,6]. Genetic models, especially KO/CKO mouse models, have been crucial in understanding its functions.

In mice, disruption of Phactr4 gene causes colon hypoganglionosis similar to human Hirschsprung disease, with ENCCs showing migration defects due to undirected cellular protrusions. This indicates Phactr4's role in coordinating integrin signaling and cofilin activity for ENCC directional migration [3,5]. In the humpty dumpty mouse mutant, where Phactr4 is disrupted, there are failures in neural tube and optic fissure closure. This is due to abnormal cell-cycle progression caused by elevated proliferation and abnormally phosphorylated, inactive PP1 [4]. In depressed rats, upregulated Phactr4 in the CA1 hippocampus contributes to the pathogenesis of depression by suppressing the p-LIMK/p-Cofilin signaling pathway (affecting synaptic structure) and activating the NF-κB/NLRP3 pathway (promoting neuroinflammation), while downregulation alleviates depression-like behaviors [1]. In human hepatocellular carcinoma, overexpression of PHACTR4 inhibits HCC cells proliferation, colony formation, migration and invasion, acting as a tumor suppressor by inhibiting the IL-6/Stat3 pathway [2].

In conclusion, Phactr4 is essential for regulating cytoskeletal dynamics, cell-cycle progression, and neural-related functions. Mouse models have been instrumental in revealing its role in Hirschsprung-like diseases, neural tube and optic fissure development, depression-like behaviors in rats, and tumor suppression in hepatocellular carcinoma. These findings suggest that Phactr4 could be a potential target for treating related diseases.