The Atypical Cadherin Fat Directly Regulates Mitochondrial Function and Metabolic State

Sing, Anson; Tsatskis, Yonit; Fabian, Lacramioara; Hester, Ian; Rosenfeld, Robyn; Serricchio, Mauro; Yau, Norman; Bietenhader, Maïlis; Shanbhag, Riya; Jurisicova, Andrea; Brill, Julie A.; McQuibban, G. Angus; McNeill, Helen

doi:10.1016/j.cell.2014.07.036

Cited by 74 publications

(62 citation statements)

References 48 publications

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“…Interestingly, Drp1 loss in the Drosophila follicle cell layer closely phenocopies loss of Hippo signaling in the increase in CycE levels and maintenance of aberrant cell proliferation in defined cell contexts (Meignin et al, 2007;Mitra et al, 2012). Moreover, recent studies indicate that various aspects of the Hippo pathway involve mitochondria (Sing et al, 2014;Ohsawa et al, 2012;Del Re et al, 2014;Nagaraj et al, 2012). Therefore, directed studies to investigate the interplay …”

Section: Discussionmentioning

confidence: 99%

A novel mitochondrial pool of Cyclin E, regulated by Drp1, is linked to cell density dependent cell proliferation

Parker

Iyer

Shah

et al. 2015

Journal of Cell Science

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The regulation and function of the crucial cell cycle regulator cyclin E (CycE) remains elusive. Unlike other cyclins, CycE can be uniquely controlled by mitochondrial energetics, the exact mechanism being unclear. Using mammalian cells (in vitro) and Drosophila (in vivo) model systems in parallel, we show that CycE can be directly regulated by mitochondria through its recruitment to the organelle. Active mitochondrial bioenergetics maintains a distinct mitochondrial pool of CycE (mtCycE) lacking a key phosphorylation required for its degradation. Loss of the mitochondrial fission protein dynaminrelated protein 1 (Drp1, SwissProt O00429 in humans) augments mitochondrial respiration and elevates the mtCycE pool allowing CycE deregulation, cell cycle alterations and enrichment of stem cell markers. Such CycE deregulation after Drp1 loss attenuates cell proliferation in low-cell-density environments. However, in high-celldensity environments, elevated MEK-ERK signaling in the absence of Drp1 releases mtCycE to support escape of contact inhibition and maintain aberrant cell proliferation. Such Drp1-driven regulation of CycE recruitment to mitochondria might be a mechanism to modulate CycE degradation during normal developmental processes as well as in tumorigenic events.

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Section: Discussionmentioning

confidence: 99%

A novel mitochondrial pool of Cyclin E, regulated by Drp1, is linked to cell density dependent cell proliferation

Parker

Iyer

Shah

et al. 2015

Journal of Cell Science

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“…In Drosophila there are two Fat family cadherins: Fat and Fat-like (Kugelei -FlyBase). Fat regulates PCP, and restricts tissue growth through the Hippo pathway (reviewed by Sopko and McNeill, 2009;Staley and Irvine, 2012) and via regulation of metabolism (Sing et al, 2014). It has been proposed that Fat binding to another atypical cadherin, Dachsous, leads to dimerization and processing of Fat, ultimately activating an intracellular cascade (Feng and Irvine, 2009;.…”

Section: Introductionmentioning

confidence: 99%

Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development

et al. 2015

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Mammalian brain development requires coordination between neural precursor proliferation, differentiation and cellular organization to create the intricate neuronal networks of the adult brain. Here, we examined the role of the atypical cadherins Fat1 and Fat4 in this process. We show that mutation of Fat1 in mouse embryos causes defects in cranial neural tube closure, accompanied by an increase in the proliferation of cortical precursors and altered apical junctions, with perturbations in apical constriction and actin accumulation. Similarly, knockdown of Fat1 in cortical precursors by in utero electroporation leads to overproliferation of radial glial precursors. Fat1 interacts genetically with the related cadherin Fat4 to regulate these processes. Proteomic analysis reveals that Fat1 and Fat4 bind different sets of actin-regulating and junctional proteins. In vitro data suggest that Fat1 and Fat4 form cis-heterodimers, providing a mechanism for bringing together their diverse interactors. We propose a model in which Fat1 and Fat4 binding coordinates distinct pathways at apical junctions to regulate neural progenitor proliferation, neural tube closure and apical constriction.

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“…The tumor suppressors Ft and Ds encode large proto-cadherins that interact in a heterophilic manner and regulate proliferation via the Hippo/Yki pathway or mitochondrial metabolism, planar cell polarity and tissue morphogenesis by promoting oriented cell divisions and cell-cell rearrangements (Mahoney et al, 1991;Clark et al, 1995;Matakatsu and Blair, 2004;Baena-Lopez et al, 2005;Cho et al, 2006;Silva et al, 2006;Willecke et al, 2006;Harvey and Tapon, 2007;Mao et al, 2011;Donoughe and DiNardo, 2011;Bosveld et al, 2012;Brittle et al, 2012;Marcinkevicius and Zallen, 2013;Lawrence and Casal, 2013;Matis and Axelrod, 2013;Degoutin et al, 2013;Sing et al, 2014). Within tissues, opposing gradients of Ds and the Golgi resident kinase Four-jointed, which regulates Ft-Ds interaction, result in the planar polarization of Ft and Ds (Ishikawa et al, 2008;Brittle et al, 2010Brittle et al, , 2012Simon et al, 2010;Bosveld et al, 2012;Ambegaonkar et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Modulation of junction tension by tumor-suppressors and proto-oncogenes regulates cell-cell contacts

et al. 2016

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Tumor suppressors and proto-oncogenes play crucial roles in tissue proliferation. Furthermore, de-regulation of their functions is deleterious to tissue architecture and can result in the sorting of somatic rounded clones minimizing their contact with surrounding wild-type (wt) cells. Defects in the shape of somatic clones correlate with defects in proliferation, cell affinity, cell-cell adhesion, oriented cell division and cortical contractility. Combining genetics, liveimaging, laser ablation and computer simulations, we aim to analyze whether distinct or similar mechanisms can account for the common role of tumor suppressors and proto-oncogenes in cell-cell contact regulation. In Drosophila epithelia, the tumor suppressors Fat (Ft) and Dachsous (Ds) regulate cell proliferation, tissue morphogenesis, planar cell polarity and junction tension. By analyzing the evolution over time of ft mutant cells and clones, we show that ft clones reduce their cell-cell contacts with the surrounding wt tissue in the absence of concomitant cell divisions and overproliferation. This contact reduction depends on opposed changes of junction tensions in the clone bulk and its boundary with neighboring wt tissue. More generally, either clone bulk or boundary junction tension is modulated by the activation of Yorkie, Myc and Ras, yielding similar contact reductions with wt cells. Together, our data highlight mechanical roles for proto-oncogene and tumor suppressor pathways in cell-cell interactions.

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The Atypical Cadherin Fat Directly Regulates Mitochondrial Function and Metabolic State

Cited by 74 publications

References 48 publications

A novel mitochondrial pool of Cyclin E, regulated by Drp1, is linked to cell density dependent cell proliferation

A novel mitochondrial pool of Cyclin E, regulated by Drp1, is linked to cell density dependent cell proliferation

Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development

Modulation of junction tension by tumor-suppressors and proto-oncogenes regulates cell-cell contacts

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