P21 activated kinases

Rane, Chetan K.; Minden, Audrey

doi:10.4161/sgtp.28003

Small GTPases

2014

DOI: 10.4161/sgtp.28003

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P21 activated kinases

Chetan K. Rane¹,

Audrey Minden²

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Cited by 189 publications

(100 citation statements)

References 146 publications

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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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confidence: 99%

“…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%

“…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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confidence: 99%

“…However, knockout mice revealed distinct functions for either kinase. Upon loss of PAK1, mice display reduced mast cell degranulation and disturbed glucose homeostasis (Allen et al , 2009; Wang et al , 2011; Rane & Minden, 2014). Mice deficient for PAK2 die on embryonic day E8.5 due to defects in endothelial development (Hofmann et al , 2004; Radu et al , 2015).…”

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confidence: 99%

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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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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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

et al. 2017

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TLK1‐mediated MK5‐S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies

et al. 2022

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Metastases account for the majority of prostate cancer (PCa) deaths, and targeting them is a major goal of systemic therapy. We identified a novel interaction between two kinases: tousled-like kinase 1 (TLK1) and MAP kinase-activated protein kinase 5 (MK5) that promotes PCa spread. In PCa progression, TLK1-MK5 signalling appears to increase following antiandrogen treatment and in metastatic castration-resistant prostate cancer (mCRPC) patients. Determinations of motility rates (2D and 3D) of different TLK1-and MK5-perturbed cells, including knockout (KO) and knockdown (KD), as well as the use of specific inhibitors, showed the importance of these two proteins for in vitro dissemination. We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. Expression of MK5-S354A or kinase-dead MK5 in MK5-depleted mouse embryonic fibroblast (MEF) cells failed to restore their motility compared with that of wild-type (WT) MK5-rescued MK5 À/À MEF cells. A pMK5-S354 antiserum was used to establish this site as an authentic TLK1 target in androgen-sensitive human prostate adenocarcinoma (LNCaP) cells, and was used in immunohistochemistry (IHC) studies of age-related PCa sections from TRAMP (transgenic adenocarcinoma of the mouse prostate) mice and to probe a human tissue microarray (TMA), which revealed pMK5-S354 level is correlated with disease progression (Gleason score and nodal metastases). In addition, The Cancer Genome Atlas (TCGA) analyses of PCa expression and genome-wide association study (GWAS) relations identify TLK1 and MK5 as potential drivers of advanced PCa and as markers of mCRPC. Our work suggests that TLK1-MK5 signalling is functionally involved in driving PCa cell motility and clinical features of aggressiveness; hence, disruption of this axis may inhibit the metastatic spread of PCa.

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PAK1 c.1409 T > a (p. Leu470Gln) de novo variant affects the protein kinase domain, leading to epilepsy, macrocephaly, spastic quadriplegia, and hydrocephalus: Case report and review of the literature

Corriveau

Amaya

Koebel

et al. 2023

American J of Med Genetics Pt A

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The p‐21‐activated kinase 1 (PAK1) protein, encoded by the PAK1 gene, is an evolutionarily conserved serine/threonine‐protein kinase that regulates key cellular developmental processes. To date, seven de novo PAK1 variants have been reported to cause the Intellectual Developmental Disorder with Macrocephaly, Seizures, and Speech Delay (IDDMSSD). In addition to the namesake features, other common characteristics include structural brain anomalies, delayed development, hypotonia, and dysmorphic features. Here, we report a de novo PAK1 NM_002576.5: c.1409 T > A variant (p.Leu470Gln) identified by trio genome sequencing (GS) in a 13‐year‐old boy with postnatal macrocephaly, obstructive hydrocephalus, medically refractory epilepsy, spastic quadriplegia, white matter hyperintensities, profound developmental disabilities, and a horseshoe kidney. This is the first recurrently affected residue identified in the protein kinase domain. Combined assessment of the eight pathogenic PAK1 missense variants reveal that the variants cluster in either the protein kinase or autoregulatory domains. Although interpretation of the phenotypic spectrum is limited by the sample size, neuroanatomical alterations were found more often in individuals with PAK1 variants in the autoregulatory domain. In contrast, non‐neurological comorbidities were found more often in individuals with PAK1 variants in the protein kinase domain. Together, these findings expand the clinical spectrum of PAK1‐associated IDDMSSD and reveal potential correlations with the affected protein domains.

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P21 activated kinases

Cited by 189 publications

References 146 publications

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

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

TLK1‐mediated MK5‐S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies

PAK1 c.1409 T > a (p. Leu470Gln) de novo variant affects the protein kinase domain, leading to epilepsy, macrocephaly, spastic quadriplegia, and hydrocephalus: Case report and review of the literature

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P21 activated kinases

Cited by 189 publications

References 146 publications

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

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

TLK1‐mediated MK5‐S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies

PAK1 c.1409 T > a (p. Leu470Gln) de novo variant affects the protein kinase domain, leading to epilepsy, macrocephaly, spastic quadriplegia, and hydrocephalus: Case report and review of the literature

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

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