Drosophila Activated Cdc42 Kinase Has an Anti-Apoptotic Function

Schoenherr, Jessica A.; Drennan, J. M.; Martinez, Juan S.; Chikka, Madhusudana Rao; Hall, Mark C.; Chang, Henry; Clemens, James C.

doi:10.1371/journal.pgen.1002725

Cited by 18 publications

(20 citation statements)

References 59 publications

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“…As depletion of hpo kinase results in the hyperactivation of Yki, we hypothesized that the abrogated eye development observed in ey4hpo-RNAi or ey4wts-RNAi flies grown on caffeine was a consequence of increased Yki activity. As previously reported, 49 eye-specific overexpression of yki causes overgrowth of eye tissue (Figure 4d). When flies of the same genotype were reared on caffeine food, they displayed abnormally round eyes, which were also rough and appeared to contain less pigment, suggesting that caffeine exposure reduced the eye overgrowth phenotype because of increased apoptosis (Figure 4d).…”

Section: Resultssupporting

confidence: 88%

The Hippo pathway promotes cell survival in response to chemical stress

Cara

Maile²,

Parsons

et al. 2015

Cell Death Differ

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Cellular stress defense mechanisms have evolved to maintain homeostasis in response to a broad variety of environmental challenges. Stress signaling pathways activate multiple cellular programs that range from the activation of survival pathways to the initiation of cell death when cells are damaged beyond repair. To identify novel players acting in stress response pathways, we conducted a cell culture RNA interference (RNAi) screen using caffeine as a xenobiotic stress-inducing agent, as this compound is a well-established inducer of detoxification response pathways. Specifically, we examined how caffeine affects cell survival when Drosophila kinases and phosphatases were depleted via RNAi. Using this approach, we identified and validated 10 kinases and 4 phosphatases that are essential for cell survival under caffeine-induced stress both in cell culture and living flies. Remarkably, our screen yielded an enrichment of Hippo pathway components, indicating that this pathway regulates cellular stress responses. Indeed, we show that the Hippo pathway acts as a potent repressor of stress-induced cell death. Further, we demonstrate that Hippo activation is necessary to inhibit a pro-apoptotic program triggered by the interaction of the transcriptional co-activator Yki with the transcription factor p53 in response to a range of stress stimuli. Our in vitro and in vivo loss-of-function data therefore implicate Hippo signaling in the transduction of cellular survival signals in response to chemical stress. Throughout their lives, organisms are exposed to a wide range of harmful substances. These compounds, often referred to as xenobiotics, may enter the body through direct contact, inhalation or ingestion, and can originate from many sources including pharmaceuticals, pesticides, plant toxins and pollutants. The ubiquitous and varied nature of xenobiotic pressure is reflected in the complexity of conserved cellular defense mechanisms that respond to these chemical compounds, and metazoans have thus developed a range of pathways that activate survival responses or trigger programmed cell death to eliminate damaged cells. 1 Xenobiotic pathways control the expression and activation of heat shock proteins, oxidative stress components, DNA repair enzymes, hypoxia response factors and several groups of xenobiotic-metabolizing enzymes. In eukaryotes, environmental challenges that activate stress response programs are relayed through a complex signaling cascade. Some stress pathways respond to very specific compounds, whereas others, such as those depending on Mitogen-activated protein kinases, propagate stress signals from a broad spectrum of stimuli. 1-3 Despite the importance that stress response pathways play in pharmacology and toxicology, we still have a relatively poor understanding of the complex networks that launch these cellular defense systems.We performed a quantitative cell-culture RNA interference (RNAi) assay of Drosophila kinases and phosphatases to identify key regulators of stress response pathways that reac...

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Section: Resultssupporting

confidence: 88%

The Hippo pathway promotes cell survival in response to chemical stress

Cara

Maile²,

Parsons

et al. 2015

Cell Death Differ

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“…While Hsp26 has no effect on fl y survival to hid-, reaper-and grim-induced lethality when over-expressed in neurons (Liao et al 2008 ), it was shown to interact with activated Cdc42 kinase (ack) together with Hsp23 and some other proteins in an affi nity assay on S2 cells (Schoenherr et al 2012 ). Ack is an anti-apoptotic protein, which blocks programmed cell death induced by hid and reaper.…”

Section: Shsps and Apoptosismentioning

confidence: 99%

“…Ack is an anti-apoptotic protein, which blocks programmed cell death induced by hid and reaper. While the knockdown of Hsp23 had no effect on ack anti-apoptotic activity, the knockdown of Hsp26 was shown to suppress this activity (Schoenherr et al 2012 ). These results demonstrate the distinctive features of Drosophila sHsps and suggest that Hsp26 functions directly with ack or in a parallel pathway to regulate survival.…”

Section: Shsps and Apoptosismentioning

confidence: 99%

Drosophila Small Heat Shock Proteins: An Update on Their Features and Functions

Morrow¹,

Tanguay²

2015

Heat Shock Proteins

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Small heat shock proteins (sHsps) are present in varying numbers in all organisms. In Drosophila melanogaster there are 12 sHsps, which have distinctive developmental expression patterns, intracellular localizations and substrate specifi cities. Even if most of Drosophila sHsps do not have a known mammalian ortholog, they share their involvement in multiple cellular processes such as cytoskeleton modulation, apoptosis and autophagy. New data on Drosophila sHsps have arisen from high-throughput genomic and proteomic studies as well as from deletion experiments. In addition to showing the complexity of this family, these experiments suggest the involvement of sHsps in new cellular processes such as the involvement of Hsp27 in piRNA biosynthesis. The goal of this review is to summarize the new fi ndings on each Drosophila sHsp and to highlight its similarity to other sHsps as well as its distinctive features.

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“…Most mammalian cells undergo cell cycle arrest followed by apoptosis when ACK1 protein is depleted by silencing RNA, or when treated with ACK1-specific small molecule inhibitors [19; 20; 35]. The pro-proliferative function of ACK1 like proteins is conserved in the fruit fly, Drosophila [36]. Drosophila Ack resembles human TNK1 in domain organization, but retains significant sequence identity/similarity with ACK1/TNK2 in all conserved domains including the activation loop [36].…”

Section: Introductionmentioning

confidence: 99%

“…The pro-proliferative function of ACK1 like proteins is conserved in the fruit fly, Drosophila [36]. Drosophila Ack resembles human TNK1 in domain organization, but retains significant sequence identity/similarity with ACK1/TNK2 in all conserved domains including the activation loop [36]. While homozygous female flies with Ack 86 null alleles are normal, the males are sterile.…”

Section: Introductionmentioning

confidence: 99%

ACK1 tyrosine kinase: Targeted inhibition to block cancer cell proliferation

Mahajan

2013

Cancer Letters

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ACK1 tyrosine kinase, located on chromosome 3q29, is aberrantly activated, amplified or mutated in a wide variety of human cancers. While the deregulated kinase is oncogenic and its activation correlates with progression to metastatic stage, its inhibition causes cell cycle arrest, sensitizes cells to ionizing radiation and induces apoptosis. Oncogenicity of ACK1 is not only due to its ability to promote activation of critical pro-survival kinases and receptors by phosphorylating at distinct tyrosine residues, but also by employing a similar mechanism to eliminate a tumor suppressor from cancer cells. Despite the substantial data supporting the oncogenic role of ACK1, and the potential clinical benefit of blocking ACK1 in metastatic disease, to date ACK1-specific small molecule inhibitors have not been exploited for cancer therapy. This review highlights recent advances that elucidate how cancer cells employ ACK1 kinase to their advantage and discusses some of the novel ACK1 inhibitors that have shown promise in pre-clinical studies.

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Drosophila Activated Cdc42 Kinase Has an Anti-Apoptotic Function

Cited by 18 publications

References 59 publications

The Hippo pathway promotes cell survival in response to chemical stress

The Hippo pathway promotes cell survival in response to chemical stress

Drosophila Small Heat Shock Proteins: An Update on Their Features and Functions

ACK1 tyrosine kinase: Targeted inhibition to block cancer cell proliferation

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