The Role of p21-Activated Kinases in Cancer and Beyond: Where Are We Heading?

Hui Liu,Kangdong Liu,Zigang Dong

doi:10.3389/fcell.2021.641381

Abstract

The p21-activated kinases (PAKs), downstream effectors of Ras-related Rho GTPase Cdc42 and Rac, are serine/threonine kinases. Biologically, PAKs participate in various cellular processes, including growth, apoptosis, mitosis, immune response, motility, inflammation, and gene expression, making PAKs the nexus of several pathogenic and oncogenic signaling pathways. PAKs were proved to play critical roles in human diseases, including cancer, infectious diseases, neurological disorders, diabetes, pancreatic acinar diseases, and cardiac disorders. In this review, we systematically discuss the structure, function, alteration, and molecular mechanisms of PAKs that are involved in the pathogenic and oncogenic effects, as well as PAK inhibitors, which may be developed and deployed in cancer therapy, anti-viral infection, and other diseases. Furthermore, we highlight the critical questions of PAKs in future research, which provide an opportunity to offer input and guidance on new directions for PAKs in pathogenic, oncogenic, and drug discovery research.

Highlights

Various protein kinases have been identified to be drivers in human cancer progression, and targeting oncogenic protein kinases has been developed successfully for cancer therapy
The CCK-stimulated PAK2 has been proved to be mediated by the activation of CDC42/Rac1, PKC, and Src in rat pancreatic acinar cells (Nuche-Berenguer and Jensen, 2015). This activation of PAK2 stimulates several signal cascades including MAPK, FAK, and PI3K–Akt pathways to mediate physiological or pathophysiological responses related to the onset of pancreatitis, which can be inhibited by a p21-activated kinases (PAKs) inhibitor, suggesting that PAK2 can act as a new therapeutic target for the treatment of pancreatic acinar diseases (Nuche-Berenguer et al, 2016)
PAK inhibitors are proved to be effective in PAK-related diseases

Summary

Introduction

Various protein kinases have been identified to be drivers in human cancer progression, and targeting oncogenic protein kinases has been developed successfully for cancer therapy. Some small molecular compounds have been developed as PAK inhibitors for cancer restriction, infectious diseases, including SARS and SARS-CoV-2, mental retardation (MR), cardiac disorders, diabetes, and pancreatic acinar disease therapy (Maruta and He, 2020). We summarize the structure, function, alteration, and molecular mechanisms of different PAKs that involved in the cancer development, pathogenic progression, and infection.

Results

Conclusion