PAK4

Official Full Name

p21 (RAC1) activated kinase 4

Organism

Homo sapiens

GeneID

10298

Background

PAK proteins, a family of serine/threonine p21-activating kinases, include PAK1, PAK2, PAK3 and PAK4. PAK proteins are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. They serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK4 interacts specifically with the GTP-bound form of Cdc42Hs and weakly activates the JNK family of MAP kinases. PAK4 is a mediator of filopodia formation and may play a role in the reorganization of the actin cytoskeleton. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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Detailed Information

Role of PAK4 in immune system and its potential usage in cancer immunotherapy

The downstream effector of Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 homolog (CDC42), PAK4 is located at the locus 19q13.2 and the first one to be cloned in the group B PAKs. Unlike the other PAKs, PAK4 us effector loop mutant CDC42C40 interacted. in spite of its important role in embryonic viability and tissue development, down-regulation of it can be seen adult tissues. Kinase dependent or independent mechanisms of PAK4 for cell survival maintenance and apoptotic cell death protection were demonstrated in several studies. Over-expression of PAK4 in human cells showed a pro-oncogenic function, which can only be seen in this PAK family member. More than this, there is an implication of high levels of PAK4 in carcinogenesis for its affection in numerous biological processes including cell proliferation, survival and migration. Gene amplification may be the cause of PAK4 over-expression in tumor cells, since 19q13.2 locus is frequently amplified in many cancer types. So based on those findings, PAK4 expression may be put forward towards the usage of excellent diagnostic tool for embryo of tumor development. And PAK4 expression inhibition has also be recently demonstrated to be able to improve responses to anti-PD1 therapy in murine models of renal cancer and melanoma.

PAK4 acts as a cancer immune-evasion target

Up-regulation of PD-L1 by tumor cells and immune cells is accompanied with ongoing anti-tumor immune response, and it can in turn suppresses CD8+ T cell activity. Once the establishment of the immune infiltrate in the tumor microenvironment, PD-1-PD-L1 axis targeted checkpoint-blockade therapy can be used to lift T cell inhibition, thus leading to tumor control and therapeutic response. Wnt-β-catenin signaling resulted from tumor-cell-intrinsic PAK4 signaling, for which can lead to the phosphorylation and nuclear translocation of the transcription factor β-catenin. Immune exclusion and fewer T cells and dendritic cells (DCs) in the tumor led by Wnt/β-catenin signaling render anti-PD-1 ineffective without existing immune infiltrate. CRISPR-Cas9 ablation or pharmacological inhibition of PAK4 can decrease Wnt-pathway activity and lead to increased T cell tumor infiltration, thus lifting anti-PD-1 efficacy.

Figure 1. PAK4-mediated signaling pathways in PD. (So-Yoon Won, et al. 2019)

References:

Naїja A, Merhi M, Inchakalody V, et al. The role of PAK4 in the immune system and its potential implication in cancer immunotherapy. Cellular immunology, 2021, 367: 104408.
Won S Y, Park J J, Shin E Y, et al. PAK4 signaling in health and disease: Defining the PAK4–CREB axis. Experimental & Molecular Medicine, 2019, 51(2): 1-9.

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