p21-activated kinases in cancer

Key Points

  • p21 activated kinases (Paks) are a family of conserved non-receptor serine/threonine kinases that integrate various signalling pathways that are vital to normal cell survival and function.

  • PAK1 is essential for cell transformation that is induced by various oncogenes, and PAK1 and PAK4 are upregulated and activated in several human tumour types.

  • Paks elicit their biological effects mainly through the activity of interacting proteins or kinase substrates that are involved in multiple cell-regulatory pathways that contribute to cell transformation and tumour-cell invasion.

  • Paks modulate the expression of genes for both survival and metastatic potential through transcriptional modulator substrates and by their association with nuclear chromatin.

  • Demonstration of a role for Paks in tumour development and/or maintenance of invasive phenotypes provides another potential strategy for the development of targeted therapies against Paks and their downstream effectors.

  • Drug-discovery efforts have led to the development of several direct and indirect inhibitors of Paks that could potentially be used as anticancer therapeutics.

Abstract

The pivotal role of kinases in signal transduction and cellular regulation has lent them considerable appeal as pharmacological targets across a broad spectrum of cancers. p21-activated kinases (Paks) are serine/threonine kinases that function as downstream nodes for various oncogenic signalling pathways. Paks are well-known regulators of cytoskeletal remodelling and cell motility, but have recently also been shown to promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, which results in tumour formation and cell invasiveness. Alterations in Pak expression have been detected in human tumours, which makes them an attractive new therapeutic target.

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Figure 1: Modes of PAK1 regulation in normal and cancer cells.
Figure 2: Downstream signalling effectors of PAK1.

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Acknowledgements

We thank our colleagues for sharing their unpublished observations and we apologize to several of our colleagues for not citing their primary references owing to space limitation. The work in the Kumar laboratory is supported by the US National Institutes of Health (NIH).

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Glossary

Filopodia

Thin protusions from a cell that drive directional cell motility.

Lamellipodia

Broad projections at the leading edge of a motile cell that show highly dynamic behaviour that is characterized by rapid extension and retraction.

Hyperplastic nodules

Hyperplastic nodules are formed by the increased growth of normal cells and are classified as precursor lesions to mammary cancer.

Intraductal neoplasia

Non-cancerous growth of the cells lining the internal and external surfaces of the mammary gland. It is an important sign that breast cancer could develop.

Tamoxifen

Tamoxifen is an anti-oestrogen drug that is widely used as adjuvant therapy for oestrogen receptor (ER)-positive breast tumours.

Microtubule-organizing centres

A structure that is found in all plant and animal cells from which microtubules radiate. In the context of animal cells, the microtubule-organizing centre is the centrosome that usually has a pair of centrioles and is found near the nucleus.

Spindle fibres

Clusters of microtubules that grow out from each centrosome with their plus ends growing towards the metaphase plate during mitosis.

Chromosomal-segregation defects

Defects that arise in daughter cells during the process of physical partition of replicated and aligned chromosomes by the bipolar mitotic spindle during mitosis.

Cell aneuploidy

Having one or more extra (or fewer) chromosomes than the normal diploid (2n) set (for example, 2n+1, 2n − 1).

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Kumar, R., Gururaj, A. & Barnes, C. p21-activated kinases in cancer. Nat Rev Cancer 6, 459–471 (2006). https://doi.org/10.1038/nrc1892

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