Pak4, also known as p21-activated kinase 4, is a member of the serine-threonine kinase family. It functions downstream of the Rho GTPases cdc42 and Rac1, regulating numerous cellular physiological processes like cell adhesion, migration, proliferation, and survival [2,6]. It is involved in multiple signaling pathways, such as those related to focal adhesion kinases, MAPK, GSK3, and β-catenin [7]. Pak4 is of great biological importance as its dysregulation contributes to various pathological conditions, especially cancer [2,5,6]. Genetic models, including KO/CKO mouse models, are valuable for studying its functions.

In diet-induced obese mice, skeletal muscle-specific Pak4 ablation retains insulin sensitivity, accompanied by AMPK activation and GLUT4 upregulation. This reveals that Pak4 promotes insulin resistance by phosphorylating AMPKα2 at Ser491, thus inhibiting AMPK activity, suggesting targeting skeletal muscle Pak4 could be a therapeutic approach for type 2 diabetes [1]. In glioblastoma, PAK4 knockout in tumor endothelial cells reduces vascular abnormalities, improves T cell infiltration and inhibits tumor growth in mice, indicating that targeting PAK4-mediated endothelial cell plasticity may enhance cancer immunotherapy [3]. In colorectal cancer, knockout of CDK15 in mice, which phosphorylates PAK4 at S291, retards AOM/DSS-induced tumorigenesis, and inhibition of PAK4 reverses the tumorigenic function of CDK15, suggesting the CDK15-PAK4 axis as a potential therapeutic target [4].

In conclusion, Pak4 plays crucial roles in regulating glucose homeostasis, tumor-associated vascular microenvironment, and cancer cell proliferation. The use of Pak4 KO/CKO mouse models has provided significant insights into its functions in type 2 diabetes, glioblastoma, and colorectal cancer, highlighting its potential as a therapeutic target in these disease areas.