P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer

Abstract

The p21-Activated kinase 1 (PAK1), a member of serine-threonine kinases family, was initially identified as an interactor of the Rho GTPases RAC1 and CDC42, which affect a wide range of processes associated with cell motility, survival, metabolism, cell cycle, proliferation, transformation, stress, inflammation, and gene expression. Recently, the PAK1 has emerged as a potential therapeutic target in cancer due to its role in many oncogenic signaling pathways. Many PAK1 inhibitors have been developed as potential preclinical agents for cancer therapy. Here, we provide an overview of essential roles that PAK1 plays in cancer, including its structure and autoactivation mechanism, its crucial function from onset to progression to metastasis, metabolism, immune escape and even drug resistance in cancer; endogenous regulators; and cancer-related pathways. We also summarize the reported PAK1 small-molecule inhibitors based on their structure types and their potential application in cancer. In addition, we provide overviews on current progress and future challenges of PAK1 in cancer, hoping to provide new ideas for the diagnosis and treatment of cancer.

Keywords: PAK1; cancer; resistance; small molecular inhibitors; structure; targets.

Figure 1

PAK1 structure and the autoactivation mechanism. (A) Schematic representation of the P21-activated kinases including Group I PAKs and Group II PAKs. Of them, PAK1-3 are divvied into Group I PAKs and PAK4-7 are divvied into Group II PAKs. (B) PAK1 contains a p21-binding domain (PBD) at the N-terminus for GTPase association, an auto inhibitory domain (AID) and a C-terminal kinase domain. (C) PAK1 can be activated or inhibited by numerous regulators and inhibitors. (D) The autoactivation mechanism of PAK1 which mainly dependent on phosphorylation.

Figure 2

PAK1 in cancer progression, immunity, metabolism and drug resistance. (A) In different cancer stages, PAK1 functions properly to promote cancer progression, including regulation of cancer-related pathways, angiogenesis, tumor microenvironment remodeling, immune evasion, and apoptosis inhibition. Similarly, these effects also contribute to drug resistance in cancer therapies. (B) PAK1 can help cancer cells change their metabolic pattern to adapt to new survival environment. In addition, PAK1 can affect the vitality of immune cells and help cancer cells immune escape. (C) PAK1 promotes the resistance of cancer cells to various anti-tumor drugs through the PAK1 PPI network.

Figure 3

Endogenous upstream regulators of PAK1. (A) miRNAs and LncRNAs that involve in regulating the expression of PAK1. Of them, miRNAs target PAK1 or PAK-related proteins to regulate PAK1 expression. Moreover, LncRNAs regulate PAK1 activity via target PAK1-related miRNAs. (B) The protein interaction is another way to regulate PAK1 activity. The proteins can regulate PAK1 activity mainly through phosphorylation, acetylation, transcriptional regulation, and PPI network. The green proteins in the figure inhibit PAK1 activity and the blue proteins activate PAK1 activity.

Figure 4

PAK1 is a key molecular determinant in major cell proliferation pathways. (A) PAK1 promotes Wnt / β-catenin signaling via activating β-catenin. The activation of β-catenin by PAK1 is mainly through direct phosphorylation and PAK1-AKT-GSK-3β pathway. After activation, β-catenin translocates to the nucleus and activates the transcription of a series of oncogenes, such as MYC and MMPs. (B) PAK1 is at the core of EGFR/HER2/MAPK pathways, and PAK1 precisely regulates EGFR/HER2/MAPK network to regulate cancer cell.

Figure 5

PAK1 plays a central role in apoptosis and NF-κB pathways. PAK1 can inhibit apoptosis through Raf1 and DLC1 regulated Bim inhibition and Bcl-2 activation. In addition, PAK1 stimulate JNK-IκB-RelA and NIK-IKKα-RelB/p52 pathways to promote inflammation to promote cancer cell proliferation, migration and survival.

Figure 6

PAK1 contributes a lot in cell cycle progression. PAK1 triggers cell cycle progression through phosphorylation of some substrate proteins, including AuroraA, Arpc1b, PLK1, histone H3, MORC2, NF-κB and c-Raf. In addition, PAK1 activates Myc to stimulate the activity of CDK2/CyclinE and CDK4/6/CyclinD to promote cell cycle profression. Moreover, PAK1 can regulate tubulin polymerization and polymerization via TCoB and MACK to play a role in cell cycle regulation.

Figure 7

PAK1 in autophagy pathways. PAK1 regulates autophagy via direct or indirect regulation. Acetylation of PAK1 could phosphorylate ATG5 to inhibit its ubiquitination-dependent degradation to promote autophagy. In addition, PAK1-AKT-mTOR signaling is another key pathway that involved in PAK1-regulated autophagy. Moreover, PAK1-mediated autophagy-related genes expression is also contribute to autophagy regulation.

Figure 8

PAK1 fine-tuning the PPI network to accelerate cancer EMT and metastasis. PAK1 can activate Wnt/β-catenin, PI3K-AKT, Ras-MAPK, JNK and NF-κB pathways to promote the transcription of twist, snail and slug. These EMT-promoting transcription factors promote the expression of MMPs, while inhibit the expression of epithelial cell specific protein, such as E-cadherin to promote cancer EMT and metastasis.

Figure 9

The crosstalk between PAK1 and other cancer-related pathways. PAK1 can also regulate the proliferation and cytoskeletal movement of cancer cells via crosstalk with the Hippo-YAP signaling pathway and the TGF-β signaling pathway. In addition, PAK1 can promote tumorigenesis and angiogenesis through Notch and STAT5 signaling pathways activation.