PP2AT61ɛ Is an Inhibitor of MAP4K3 in Nutrient Signaling to mTOR

Yan, Lijun; Mieulet, Virginie; Burgess, Darren J.; Findlay, Greg M.; Sully, Katherine; Procter, Julia; Goris, Jozef; Janssens, Veerle; Morrice, Nick; Lamb, Richard F.

doi:10.1016/j.molcel.2010.01.031

Cited by 113 publications

(95 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we present the murine KO of PR61/B'δ, a member of PR61/B', the largest PP2A B-type subunit family with multiple roles in cellular signaling (2,29,30). Despite high embryonic PR61/B'δ expression in WT mice (7), PR61/B'δ KO mice are viable and fertile, with normal placental development and trophoblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

Mice lacking phosphatase PP2A subunit PR61/B’δ ( Ppp2r5d ) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β

Louis

Martens

Borghgraef

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

109

106

View full text Add to dashboard Cite

Functional diversity of protein phosphatase 2A (PP2A) enzymes mainly results from their association with distinct regulatory subunits. To analyze the functions of one such holoenzyme in vivo, we generated mice lacking PR61/B'δ (B56δ), a subunit highly expressed in neural tissues. In PR61/B'δ-null mice the microtubule-associated protein tau becomes progressively phosphorylated at pathological epitopes in restricted brain areas, with marked immunoreactivity for the misfolded MC1-conformation but without neurofibrillary tangle formation. Behavioral tests indicated impaired sensorimotor but normal cognitive functions. These phenotypical characteristics were further underscored in PR61/B'δ-null mice mildly overexpressing human tau. PR61/B'δ-containing PP2A (PP2A T61δ ) poorly dephosphorylates tau in vitro, arguing against a direct dephosphorylation defect. Rather, the activity of glycogen synthase kinase-3β, a major tau kinase, was found increased, with decreased phosphorylation of Ser-9, a putative cyclin-dependent kinase 5 (CDK5) target. Accordingly, CDK5 activity is decreased, and its cellular activator p35, strikingly absent in the affected brain areas. As opposed to tau, p35 is an excellent PP2A T61δ substrate. Our data imply a nonredundant function for PR61/B'δ in phospho-tau homeostasis via an unexpected spatially restricted mechanism preventing p35 hyperphosphorylation and its subsequent degradation.brain stem | knockout mouse | AT8 | AT180 | transgenic

show abstract

Section: Discussionmentioning

confidence: 99%

Mice lacking phosphatase PP2A subunit PR61/B’δ ( Ppp2r5d ) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β

Louis

Martens

Borghgraef

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

109

106

View full text Add to dashboard Cite

show abstract

“…kinase (phosphatylinosotol 3-kinase) Nobukuni et al, 2005;Findlay et al, 2007;Juhasz et al, 2008;Yan et al, 2010). However, additional studies are needed to clarify the roles of these proteins in TORC1 activation.…”

Section: Amino Acidsmentioning

confidence: 99%

“…Surprisingly, the sensitivity of TORC1 to amino acids persists in TSC-null cells (Smith et al, 2005). Proteins with a purported role in TORC1 nutrient sensitivity are Ste20-related kinase MAP4K3 (mitogenactivated protein kinase kinase kinase kinase 3) and the VPS34 DEVELOPMENT 3346 kinase (phosphatylinosotol 3-kinase) Nobukuni et al, 2005;Findlay et al, 2007; Juhasz et al, 2008;Yan et al, 2010). However, additional studies are needed to clarify the roles of these proteins in TORC1 activation.…”

mentioning

confidence: 99%

An emerging role for TOR signaling in mammalian tissue and stem cell physiology

2011

View full text Add to dashboard Cite

SummaryThe mammalian target of rapamycin (mTOR) is a kinase that responds to a myriad of signals, ranging from nutrient availability and energy status, to cellular stressors, oxygen sensors and growth factors. The finely tuned response of mTOR to these stimuli results in alterations to cell metabolism and cell growth. Recent studies of conditional knockouts of mTOR pathway components in mice have affirmed the role of mTOR signaling in energy balance, both at the cell and whole organism levels. Such studies have also highlighted a role for mTOR in stem cell homeostasis and lifespan determination. Here, we discuss the molecular mechanisms of TOR signaling and review recent in vitro and in vivo studies of mTOR tissuespecific activities in mammals. Key words: mTOR, TORC1, Stem cells, Rapamycin, TSC IntroductionThe ability of cells to respond appropriately to nutrient flux is essential for maintaining energy homeostasis. From yeast to humans, nutrient deprivation activates a highly conserved cellular program that acts to prune back energy-intensive processes while promoting energy-producing catabolic activities. Target of rapamycin (TOR) is a key regulatory kinase that acts at the nexus of a vast array of nutrient-sensitive signals to regulate cellular metabolism. TOR exists in two complexes, TOR complex 1 (TORC1) and TOR complex 2 (TORC2), which are functionally conserved in eukaryotes. TORC1 is the primary effector for the nutrient-sensitive functions of TOR, whereas TORC2 has been implicated in cytoskeletal reorganization and cell survival. During periods of nutrient deprivation, TORC1 activity in vitro is drastically reduced, resulting in the modulation of several key processes, including translational initiation, ribosome and tRNA biogenesis, and autophagy. Key upstream regulators of TORC1 include AKT (a serine/threonine protein kinase) and the tuberous sclerosis complex (TSC). More recently, the activity of Rag GTPases in concert with Ras homolog enriched in brain (Rheb) has been described in the promotion of TORC1 activity in vitro by amino acids. These studies have filled in a major gap in our understanding of how intracellular nutrients regulate TOR activity. However, our understanding of TOR signaling in vivo has progressed more slowly. Deletion of TOR is lethal in all eukaryotic model systems, making the study of TOR signaling in vivo more challenging. Deletion of mTOR in mice, for example, is early embryonic lethal; however, conditional knockouts of mTOR or TORC components in mice have begun to reveal exciting functions for mTOR in metabolically sensitive organs. In this review, we introduce our current understanding of TOR signaling in vitro and highlight recent advances in this field. Moreover, we review recent genetic studies in mice that explore perturbation of mTOR pathway components. Finally, we discuss several recent studies that have identified a role for TOR signaling in various stem cell models. TOR kinaseThe discovery of TOR kinases arose from the study of the antifungal agent rapamycin. Additi...

show abstract

“…MAP4K3 is a positive regulator of amino acid-mTORC1 signaling (Findlay et al, 2007;Yan et al, 2010). Amino acids stimulate the activity of MAP4K3 in Drosophila and mammalian cells (Findlay et al, 2007).…”

Section: Regulators Of Rag Gtpasesmentioning

confidence: 99%

dRAGging Amino Acid-mTORC1 Signaling by SH3BP4

Kim

2013

Molecules and Cells

View full text Add to dashboard Cite

PP2AT61ɛ Is an Inhibitor of MAP4K3 in Nutrient Signaling to mTOR

Cited by 113 publications

References 33 publications

Mice lacking phosphatase PP2A subunit PR61/B’δ ( Ppp2r5d ) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β

Mice lacking phosphatase PP2A subunit PR61/B’δ ( Ppp2r5d ) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β

An emerging role for TOR signaling in mammalian tissue and stem cell physiology

dRAGging Amino Acid-mTORC1 Signaling by SH3BP4

Contact Info

Product

Resources

About