The Conserved Misshapen-Warts-Yorkie Pathway Acts in Enteroblasts to Regulate Intestinal Stem Cells in Drosophila

Li, Qi; Li, Shuangxi; Mana‐Capelli, Sebastian; Flach, Rachel J. Roth; Danai, Laura V.; Amcheslavsky, Alla; Nie, Yulun; Kaneko, Satoshi; Yao, Xiaohao; Chen, Xiaochu; Cotton, Jennifer L.; Mao, Junhao; McCollum, Dannel; Jen, Jin; Czech, Michael P.; Xu, Lan; Ip, Y. Tony

doi:10.1016/j.devcel.2014.09.012

Cited by 125 publications

(151 citation statements)

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“…Animals were maintained under conditions of a 12-h-light/12-h-dark cycle and fed standard chow (LabDiet 5P76) unless otherwise stated. Mice with conditional Map4k4 floxed alleles were generated as described elsewhere (11) and were backcrossed to C57BL/6J mice for at least 7 generations. To inactivate Map4k4 in adult mice, homozygous Map4k4 flox/flox animals were crossed to B6.CgTg(UBC-cre/ERT2)1Ejb/J mice (Jackson Laboratories).…”

Section: Methodsmentioning

confidence: 99%

Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues

Danai

Flach

Virbasius

et al. 2015

Molecular and Cellular Biology

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bStudies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body Map4k4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced Map4k4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional Map4k4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with Map4k4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) Map4k4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) Map4k4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes. Whole-body glucose homeostasis in humans is maintained by an elaborate physiological system that involves multiorgan regulation. In the postprandial state, glucose and amino acids induce ␤ cells in the pancreas to secrete insulin, promoting glucose uptake in skeletal muscle and adipose tissue while suppressing glucose production from the liver. These effects of insulin to maintain glucose homeostasis can be disrupted in obesity, causing an insulin-resistant state that contributes to elevated blood glucose levels and an increased incidence of type 2 diabetes (T2D) (1). While metformin (thought to mainly affect liver glucose metabolism) and insulin secretagogues are clinical mainstays for the treatment of T2D, further intervention is often required (2). Due to contraindications, treatments that address the underlying peripheral insulin resistance in T2D are now limited to the use of the thiazolidinediones (TZDs), a major drug class that alleviates insulin resistance by targeting peroxisome proliferator-activated receptor gamma (PPAR␥) (3, 4). Thus, novel proteins that could be targeted with drugs to enhance peripheral insulin sensitivity would prove useful in developing therapies for T2D.In screening the adipocyte kinome for such negative regulators of insulin signaling to glucose transport in vitro, we identified mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4), a serine/threonine protein kinase with homology to Saccharomyces cerevisiae Ste20 protein kinases (5). Interestingly, single nucleotide polymorphisms (SNPs) in the Ma...

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Section: Methodsmentioning

confidence: 99%

Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues

Danai

Flach

Virbasius

et al. 2015

Molecular and Cellular Biology

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“…Phosphorylation of Wts by Hpo also requires adaptor proteins such as Mats and Merlin (Mer) to recruit Wts to the plasma membrane Yin et al 2013). Recent studies show that two other kinases, Misshapen (Msn) and Happyhour (Hppy), can activate Wts and repress Yki independently of Hpo (Li et al 2014a;Zheng et al 2015). There is evidence that, like Hpo, Hppy also phosphorylates the hydrophobic motif of Wts ).…”

Section: Core Components Of the Mammalian Hippo Pathwaymentioning

confidence: 99%

“…We and others have recently reported that MST1/2 and MAP4Ks act in parallel to phosphorylate and activate LATS1/2, and deletion of both MST1/2 and MAP4Ks is required to abolish LATS1/2 hydrophobic motif phosphorylation and activation (Li et al 2014a;Meng et al 2015;Zheng et al 2015). Regulation of MST1/2 kinase activity has been extensively studied.…”

Section: The Regulation Of Lats-activating Kinases Mst1/2 and Map4ksmentioning

confidence: 99%

“…In Drosophila, Hppy can phosphorylate Wts at the hydrophobic motif of Wts. In fact, both Hppy and Msn activate Wts kinase activities and inhibit Yki transcriptional activity, as does Hpo (Li et al 2014a;Meng et al 2015;Zheng et al 2015). Hppy homologs (MAP4K1/2/3/5) and Msn homologs (MAP4K4/6/ 7) can directly phosphorylate and activate LATS1/2 and appear to have a more important function than MST1/2 in the regulation of LATS1/2 and YAP/TAZ in mammalian cells in response to several upstream signals .…”

Section: Redefining the Hippo Pathwaymentioning

confidence: 99%

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Mechanisms of Hippo pathway regulation

2016

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The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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“…It is also conceivable, that alterations in this regulation in the context of aberrant MAP4K4 activation could result in developmental defects in the embryo and cancer initiation/ progression in the adult organism. In addition to its role in the developing organ, MAP4K4 also contributes to reshaping the adult organism, where it restricts differentiation of myoblasts into myotubes [40] or in enteroblasts, where it controls differentiation by phosphorylation of the Hippo pathway core component LATS1/2 and concomitant degradation of the transcriptional regulators YAP/TAZ [41].…”

Section: Development and Differentiationmentioning

confidence: 99%

The Ser/Thr Kinase MAP4K4 Controls Pro-Metastatic Cell Functions

Tripolitsioti¹,

Grotzer²,

Baumgärtner³

2017

J Carcinog Mutagen

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The search for novel targeted therapies for major human conditions such as diabetes, cardiovascular diseases and cancer is a slow and costly process. Progress is often hampered by poor drug efficaciousness in the patients, low selectivity/specificity of the compounds and cellular evasion mechanism that are rather common in anti-cancer therapies. This is particularly true also for compounds inhibiting kinases, which in theory are optimal targets thanks to their druggable enzymatic activity. Novel targeting strategies are needed to reduce side effects and treatment failure caused by non-specific drug function and target resistance, respectively. An ideal compound will repress the relevant kinase effector function, while leaving kinase functions that are not disease-relevant unaltered. To achieve function-specific inhibition, the molecular mechanism of the drug target that governs the pathological process, must be identified.The Ser/Thr kinase MAP4K4 is implicated in inflammatory and metabolic disorders and cancer progression. In this review, we describe the molecular effector functions of MAP4K4 that exert those activities and how they have been identified and characterized both in invertebrate organisms and mammals. We discuss how the modulation of the cellular cytoskeleton by MAP4K4 may be connected to pathological conditions such as aberrant angiogenesis and cancer metastasis, and we describe the molecular mechanisms that are so far known to be mechanistically involved in these processes.

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The Conserved Misshapen-Warts-Yorkie Pathway Acts in Enteroblasts to Regulate Intestinal Stem Cells in Drosophila

Cited by 125 publications

References 74 publications

Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues

Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues

Mechanisms of Hippo pathway regulation

The Ser/Thr Kinase MAP4K4 Controls Pro-Metastatic Cell Functions

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