Endosomal Phosphatidylinositol 3-Kinase Is Essential for Canonical GPCR Signaling

Uchida, Yoshishige; Rutaganira, Florentine U.; Jullié, Damien; Shokat, Kevan M.; Zastrow, Mark von

doi:10.1124/mol.116.106252

Cited by 9 publications

(7 citation statements)

References 43 publications

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“…We verified that the rapamycin-induced localization of 3-phosphatase or 4-phosphatase to early endosomes results in reduced endosomal PtdIns(3,4)P 2 but that of 5-phosphatase dose not ( Figure 5 E,F). The activity of FKBP-MTM1, FKBP-INPP4B, and FKBP–Inp54p has been well demonstrated in previous works [ 60 , 62 , 63 , 64 , 65 ]. We investigated if rapamycin treatment (40 nM, 5 min incubation) for lipid phosphatase targeting may indirectly affect AKT activation in our experiments, as it was shown that rapamycin inhibits mTORC1 activity acutely [ 66 ] and mTORC2 activity chronically [ 67 ].…”

Section: Resultssupporting

confidence: 66%

Endosomal mTORC2 Is Required for Phosphoinositide-Dependent AKT Activation in Platelet-Derived Growth Factor-Stimulated Glioma Cells

Kim

Heo

Brzostowski

et al. 2021

Cancers

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The serine/threonine kinase AKT is a major effector during phosphatidylinositol 3-kinase (PI3K)-driven cell signal transduction in response to extracellular stimuli. AKT activation mechanisms have been extensively studied; however, the mechanism underlying target of rapamycin complex 2 (mTORC2) phosphorylation of AKT at Ser473 in the cellular endomembrane system remains to be elucidated. Here, we demonstrate that endocytosis is required for AKT activation through phosphorylation at Ser473 via mTORC2 using platelet-derived growth factor-stimulated U87MG glioma cells. mTORC2 components are localized to early endosomes during growth factor activation, and the association of mTORC2 with early endosomes is responsible for the local activation of AKT, which is critical for specific signal transduction through glycogen synthase kinase-3 beta and forkhead box O1/O3 phosphorylation. Furthermore, endosomal phosphoinositide, represented by PtdIns(3,4)P2, provides a binding platform for mTORC2 to phosphorylate AKT Ser473 in endosomes through mammalian Sty1/Spc1-interacting protein (mSIN), a pleckstrin homology domain-containing protein, and is dispensable for AKT phosphorylation at Thr308. This PtdIns(3,4)P2-mediated endosomal AKT activation provides a means to integrate PI3K activated by diverse stimuli to mTORC2 assembly. These early endosomal events induced by endocytosis, together with the previously identified AKT activation by PtdIns(3,4,5)P3, contribute to the strengthening of the transduction of AKT signaling through phosphoinositide.

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Section: Resultssupporting

confidence: 66%

Endosomal mTORC2 Is Required for Phosphoinositide-Dependent AKT Activation in Platelet-Derived Growth Factor-Stimulated Glioma Cells

Kim

Heo

Brzostowski

et al. 2021

Cancers

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“…This GPCR responds physiologically to changes in extracellular catecholamine concentration that span a wide range of time scales, through sequential bouts of Gs-coupled stimulation of cAMP production from the plasma membrane and then endosomes after agonist-induced receptor internalization 14 . Unlike polypeptide hormone receptors which are stably sequestered after endocytosis, β2ARs recycle efficiently and cycle continuously in the prolonged presence of agonist 15 , thus activating Gs transiently from each location during iterative trafficking cycles 16 . Endosomal activation has only a small effect on global cAMP elevation but is essential for efficient downstream signaling to cAMP-dependent gene transcription.…”

Section: Introductionmentioning

confidence: 99%

Spatial decoding of endosomal cAMP signals by a metastable cytoplasmic PKA network

et al. 2021

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GPCR-regulated cAMP production from endosomes can specify signaling to the nucleus by moving the source of cAMP without changing its amount. How this is possible remains unknown because cAMP gradients dissipate over the nanoscale whereas endosomes typically localize microns from the nucleus. We show that the key location-dependent step for endosome-encoded transcriptional control is nuclear entry of cAMP-dependent protein kinase (PKA) catalytic subunits. These are sourced from punctate accumulations of PKA holoenzyme that are densely distributed in the cytoplasm and titrated by global cAMP into a discrete metastable state, in which catalytic subunits are bound but dynamically exchange. Mobile endosomes containing activated receptors collide with the metastable PKA puncta and pause in close contact. We propose that these properties enable cytoplasmic PKA to act collectively like a semiconductor, converting nanoscale cAMP gradients generated from endosomes into microscale elevations of free catalytic subunit to direct downstream signaling.

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“…Similarly as in the EGFR sensing systems, the activity dynamics of these receptors is also tightly regulated by the endosomal trafficking. Even more, this regulation is mediated via PI3K, an Akt activator (Uchida et al , ). Thus, given that conditions for critical organization and maintenance in the vicinity of a SN bifurcation are also possible, it is likely that similar mechanism can confer responsiveness of GPCRs to time‐varying growth factor signals.…”

Section: Discussionmentioning

confidence: 99%

Organization at criticality enables processing of time‐varying signals by receptor networks

Stanoev

Nandan

Koseska

2020

Molecular Systems Biology

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How cells utilize surface receptors for chemoreception is a recurrent question spanning between physics and biology over the past few decades. However, the dynamical mechanism for processing time‐varying signals is still unclear. Using dynamical systems formalism to describe criticality in non‐equilibrium systems, we propose generic principle for temporal information processing through phase space trajectories using dynamic transient memory. In contrast to short‐term memory, dynamic memory generated via “ghost” attractor enables signal integration depending on stimulus history and thereby uniquely promotes integrating and interpreting complex temporal growth factor signals. We argue that this is a generic feature of receptor networks, the first layer of the cell that senses the changing environment. Using the experimentally established epidermal growth factor sensing system, we propose how recycling could provide self‐organized maintenance of the critical receptor concentration at the plasma membrane through a simple, fluctuation‐sensing mechanism. Processing of non‐stationary signals, a feature previously attributed only to neural networks, thus uniquely emerges for receptor networks organized at criticality.

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Endosomal Phosphatidylinositol 3-Kinase Is Essential for Canonical GPCR Signaling

Cited by 9 publications

References 43 publications

Endosomal mTORC2 Is Required for Phosphoinositide-Dependent AKT Activation in Platelet-Derived Growth Factor-Stimulated Glioma Cells

Endosomal mTORC2 Is Required for Phosphoinositide-Dependent AKT Activation in Platelet-Derived Growth Factor-Stimulated Glioma Cells

Spatial decoding of endosomal cAMP signals by a metastable cytoplasmic PKA network

Organization at criticality enables processing of time‐varying signals by receptor networks

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