p21-activated kinases in cancer

Kumar, Rakesh; Gururaj, Anupama E.; Barnes, Christopher J.

doi:10.1038/nrc1892

Cited by 536 publications

(563 citation statements)

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“…The p21‐activated kinases (PAKs) are conserved non‐receptor serine/threonine kinases integrating a variety of signalling pathways in biological processes, such as proliferation, apoptosis, cytoskeletal structure, and cellular motility (Hofmann et al , 2004; Kumar et al , 2006; Radu et al , 2014; Rane & Minden, 2014). PAKs are divided into group I PAKs (PAK1, PAK2, and PAK3) and group II PAKs (PAK4, PAK5, and PAK6) based on their sequence, function, and regulation.…”

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confidence: 99%

“…PAKs act downstream of oncoproteins as regulators of tumour‐specific signalling pathways (Hofmann et al , 2004; Kumar et al , 2006; Radu et al , 2014; Rane & Minden, 2014). In human cancer, PAK1 is the most frequently described and studied isoform (Kumar et al , 2006).…”

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“…In human cancer, PAK1 is the most frequently described and studied isoform (Kumar et al , 2006). Its increased activity can be caused by elevated protein levels, hyperactivation of GTPases, or downregulated expression of endogenous inhibitors (Kumar et al , 2006; Radu et al , 2014; Rane & Minden, 2014). Late stage tumours of tissues, such as brain, breast, ovary, pancreas, or colon, display increased PAK1 activity (Kumar et al , 2006).…”

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confidence: 99%

“…Its increased activity can be caused by elevated protein levels, hyperactivation of GTPases, or downregulated expression of endogenous inhibitors (Kumar et al , 2006; Radu et al , 2014; Rane & Minden, 2014). Late stage tumours of tissues, such as brain, breast, ovary, pancreas, or colon, display increased PAK1 activity (Kumar et al , 2006). In a murine MCF‐7 breast cancer model, PAK1 promoted proliferation and anchorage‐independent growth (Adam et al , 2000).…”

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confidence: 99%

“…In a murine MCF‐7 breast cancer model, PAK1 promoted proliferation and anchorage‐independent growth (Adam et al , 2000). However, in recent years, mounting evidence suggests that other PAK members also contribute to tumour formation and progression (Kumar et al , 2006; Radu et al , 2014; Rane & Minden, 2014). Gene amplification or increased levels of PAK4 were found in pancreatic cancer cells and are linked to anchorage‐independent cancer‐cell growth (Mahlamäki et al , 2004).…”

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Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1

et al. 2017

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SummaryThe p21‐activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1 + haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by shPAK2‐ but not shPAK1‐expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing PAK2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require PAK2 to grow towards an extracellular matrix. PAK2‐deficient cells fail to form colonies in methylcellulose and to induce lymphomas in vivo. PAK2 might therefore be the critical isoform in leukaemic cells by controlling tumour growth in a dual manner: vascularization via exosome‐mediated transfer to endothelial cells and remodelling of the extracellular matrix. This finding suggests that the PAK2 isoform represents a promising target for the treatment of haematological diseases.

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Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1

et al. 2017

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The Human Kinome and Kinase Inhibition

Duong‐Ly

Peterson

2013

CP Pharmacology

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Protein and lipid kinases play key regulatory roles in a number of biological processes. Unsurprisingly, activating mutations in kinases have been linked to a number of disorders and diseases, most notably cancers. Thus, kinases have emerged as promising clinical targets. There are more than 500 human protein kinases and about 20 lipid kinases. Most protein kinases share a highly conserved domain, the eukaryotic protein kinase (ePK) domain, which contains the ATP and substrate‐binding sites. Many inhibitors in clinical use bind to the highly conserved ATP binding site. For this reason, many kinase inhibitors are not exclusively selective for their intended targets. Furthermore, despite the current interest in kinase inhibitors, very few kinases implicated in disease have validated inhibitors. This unit describes the human kinome, ePK structure, and types of kinase inhibitors, focusing on methods to identify potent and selective kinase inhibitors. Curr. Protoc. Pharmacol. 60:2.9.1‐2.9.14. © 2013 by John Wiley & Sons, Inc.

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