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

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.

Quantitative Phosphoproteomics Analysis Uncovers PAK2- and CDK1-Mediated Malignant Signaling Pathways in Clear Cell Renal Cell Carcinoma

“…While especially the role of PAK1 is largely understood in different cancers, the function and targets of PAK2 remain to be elucidated (33,34). Furthermore, PAK2 has previously been noted to bind to CDK12 and thereby to activate the MAPK pathway (34). Our study shows for CDK1 and CDK5 high activity (Fig.…”

“…In addition, PAK2 is one of the few kinases that has also been experimentally detected by our proteomics approach (Supplementary Files S2 and S3), supporting its predicted elevated activity. While especially the role of PAK1 is largely understood in different cancers, the function and targets of PAK2 remain to be elucidated (33,34). Furthermore, PAK2 has previously been noted to bind to CDK12 and thereby to activate the MAPK pathway (34).…”

Potential Resistance to Antineoplastic Aminated Fullerenes Mediated by M2-Like Monocyte-Derived Exosomes

“…Upregulation of PAK expression by RAC/CDC42 induces the formation of lamellipodia, filopodia, membrane folds, and stress fibers, and the remodeling of focal adhesion complexes ( 45 ). PAK regulates cancer cell growth via several signaling pathways, including the WNT/β-catenin, EGFR/HER2/MAPK, and PI3K/AKT pathways ( 46 ). C 70 -EDA could induce G0/G1 cell cycle arrest to abrogate cancer cell proliferation ( 28 ).…”

Minor Kinases with Major Roles in Cytokinesis Regulation

“…Although some functions are shared by all six PAKs, several others are not, thus explaining the distinct types of roles in various tumors and the associated high frequency of mutation in most of them. Among PAKs, PAK1, PAK2, and PAK4 exhibit a higher expression level in most cancer types; PAK1 and PAK4 are the most studied and better characterized, yet PAK2 has the highest alteration frequency among all PAKs, especially in lung cancer [ 173 ]. In contrast, PAK6 shows both oncogenic and oncosuppressive features, depending on the cancer type.…”