Distinct functional outputs of PTEN signalling are controlled by dynamic association with β-arrestins

Lima‐Fernandes, Evelyne; Enslen, Hervé; Camand, Emeline; Kotelevets, Larissa; Boularan, Cédric; Achour, Lamia; Benmerah, Alexandre; Gibson, Lucien C.D.; Baillie, George S.; Pitcher, Julie A.; Chastre, Eric; Etienne-Manneville, Sandrine; Marullo, Stéfano; Scott, Mark G. H.

doi:10.1038/emboj.2011.178

Cited by 62 publications

(64 citation statements)

References 54 publications

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“…As proof of concept, RhoA and b-arr2, known to activate PTEN 11,22 , both promoted changes in PTEN conformation in live cells. PTEN has a number of protein-binding partners that are required for its cellular functions and plasticity 1,[48][49][50][51] .…”

Section: Discussionmentioning

confidence: 99%

“…Phosphatase assays were performed as described previously 11 . Briefly, cells were transfected with either Rluc-PTEN-YFP or YFP vector and the indicated plasmids, lysates immunoprecipitated using an anti-PTEN antibody (Millipore) or an anti-green fluorescent protein antibody (Roche) and incubated 45 min at 37°C with 100 mM water-soluble di-C8-PIP3 (Echelon Biosciences).…”

Section: Methodsmentioning

confidence: 99%

“…5c). We recently showed that b-arrs bind directly and activate PTEN lipid phosphatase activity and that this occurs downstream of RhoA/ROCK signalling 11 . We thus tested the effect of b-arr2 on PTEN conformation using the biosensor.…”

Section: Establishment and Validation Of The Rluc-pten-yfp Biosensormentioning

confidence: 99%

“…These results indicate that both positive and negative modification of signalling pathways that impact on PTEN function can be detected using the biosensor in live cells. We next investigated the effect of the RhoA/ROCK pathway on Rluc-PTEN-YFP, as the small GTPase RhoA is known to stimulate PTEN activity via its downstream effector ROCK 11,22,32 . We coexpressed the PTEN biosensor with a constitutively active form of RhoA (RhoA-V14).…”

Section: Establishment and Validation Of The Rluc-pten-yfp Biosensormentioning

confidence: 99%

“…Recently, it was shown that both mRNAs of the PTEN pseudogene, PTENP1, and competing endogenous RNAs could serve as decoys for PTEN mRNA-targeting microRNAs, inhibiting their effects on PTEN expression 7,8 . PTEN is also regulated through protein-protein interactions, the association of scaffolding proteins such as MAGI-1 and -2, NHERF and b-arrestins (b-arrs) altering its function and/or subcellular localization [9][10][11][12] . Finally, PTEN catalytic activity is regulated post-translationally by phosphorylation, acetylation, SUMOylation and ubiquitination 2,13 .…”

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confidence: 99%

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A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

et al. 2014

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Tumour suppressor PTEN is a phosphatase that negatively regulates the PI3K/AKT pathway. The ability to directly monitor PTEN conformation and function in a rapid, sensitive manner is a key step towards developing anti-cancer drugs aimed at enhancing or restoring PTEN-dependent pathways. Here we developed an intramolecular bioluminescence resonance energy transfer (BRET)-based biosensor, capable of detecting signal-dependent PTEN conformational changes in live cells. The biosensor retains intrinsic properties of PTEN, enabling structure-function and kinetic analyses. BRET shifts, indicating conformational change, were detected following mutations that disrupt intramolecular PTEN interactions, promoting plasma membrane targeting and also following physiological PTEN activation. Using the biosensor as a reporter, we uncovered PTEN activation by several G proteincoupled receptors, previously unknown as PTEN regulators. Trastuzumab, used to treat ERBB2-overexpressing breast cancers also elicited activation-associated PTEN conformational rearrangement. We propose the biosensor can be used to identify pathways regulating PTEN or molecules that enhance its anti-tumour activity.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Establishment and Validation Of The Rluc-pten-yfp Biosensormentioning

confidence: 99%

Section: Establishment and Validation Of The Rluc-pten-yfp Biosensormentioning

confidence: 99%

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confidence: 99%

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A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

et al. 2014

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Upstream regulators of phosphoinositide 3‐kinase and their role in diseases

Wang

Zhou

Chen

et al. 2019

Journal Cellular Physiology

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Phosphoinositide 3‐kinase (PI3K), a crucial signaling molecule, is regulated by various upstream regulators. Traditionally, receptor tyrosine kinases and G protein‐coupled receptor are regarded as its principle upstream regulators; however, recent reports have indicated that spleen tyrosine kinase, β‐arrestin2, Janus kinase, and RAS can also perform this role. Dysregulation of PI3K is common in the progression of various diseases, including, but not limited to, tumors, Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, and acute myelogenous leukemia. The aim of this review is to provide a perspective on PI3K‐related diseases examining both the classical and nonclassical upstream regulators of PI3K in detail.

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Inhibition of signaling downstream of beta‐2 adrenoceptor by propranolol in prostate cancer cells

et al. 2022

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Background: There is accumulating evidence that propranolol, an antagonist of beta-1 and beta-2 adrenoreceptors, extends survival of patients with prostate cancer; yet it is not known whether propranolol inhibits beta-adrenergic signaling in prostate cancer cells, or systemic effects of propranolol play the leading role in slowing down cancer progression. Recently initiated clinical studies offer a possibility to test whether administration of propranolol inhibits signaling pathways in prostate tumors, however, there is limited information on the dynamics of signaling pathways activated downstream of beta-2 adrenoreceptors in prostate cancer cells and on the inactivation of these pathways upon propranolol administration.Methods: Western blot analysis was used to test the effects of epinephrine and propranolol on activation of protein kinase (PKA) signaling in mouse prostates and PKA, extracellular signal-regulated kinase (ERK) , and protein kinase B/AKT (AKT) signaling in prostate cancer cell lines.Results: In prostate cancer cell lines epinephrine induced robust phosphorylation of PKA substrates pS133CREB and pS157VASP that was evident 2 min after treatments and lasted for 3−6 h. Epinephrine induced phosphorylation of AKT in PTEN-positive 22Rv1 cells, whereas changes of constitutive AKT phosphorylation were minimal in PTEN-negative PC3, C42, and LNCaP cells. A modest short-term increase of pERK in response to epinephrine was observed in all tested cell lines. Incubation of prostate cancer cells with 10-fold molar excess of propranolol for 30 min inhibited all downstream pathways activated by epinephrine. Subjecting mice to immobilization stress induced phosphorylation of S133CREB, whereas injection of propranolol at 1.5 mg/kg prevented the stress-induced phosphorylation.Conclusions: The analysis of pS133CREB and pS157VASP allows measuring activation of PKA signaling downstream of beta-2 adrenoreceptors. Presented results on the ratio of propranolol/epinephrine and the time needed to inhibit

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Distinct functional outputs of PTEN signalling are controlled by dynamic association with β-arrestins

Cited by 62 publications

References 54 publications

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

Upstream regulators of phosphoinositide 3‐kinase and their role in diseases

Inhibition of signaling downstream of beta‐2 adrenoceptor by propranolol in prostate cancer cells

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