Dataset Information

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

ABSTRACT: The tumour suppressor PTEN (phosphatase and tensin deleted on chromosome 10) regulates major cellular functions via lipid phosphatase-dependent and -independent mechanisms. Despite its fundamental pathophysiological importance, how PTEN's cellular activity is regulated has only been partially elucidated. We report that the scaffolding proteins ?-arrestins (?-arrs) are important regulators of PTEN. Downstream of receptor-activated RhoA/ROCK signalling, ?-arrs activate the lipid phosphatase activity of PTEN to negatively regulate Akt and cell proliferation. In contrast, following wound-induced RhoA activation, ?-arrs inhibit the lipid phosphatase-independent anti-migratory effects of PTEN. ?-arrs can thus differentially control distinct functional outputs of PTEN important for cell proliferation and migration.

SUBMITTER: Lima-Fernandes E

PROVIDER: S-EPMC3155309 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Lima-Fernandes Evelyne E Enslen Hervé H Camand Emeline E Kotelevets Larissa L Boularan Cédric C Achour Lamia L Benmerah Alexandre A Gibson Lucien C D LC Baillie George S GS Pitcher Julie A JA Chastre Eric E Etienne-Manneville Sandrine S Marullo Stefano S Scott Mark G H MG

The EMBO journal 20110603 13

The tumour suppressor PTEN (phosphatase and tensin deleted on chromosome 10) regulates major cellular functions via lipid phosphatase-dependent and -independent mechanisms. Despite its fundamental pathophysiological importance, how PTEN's cellular activity is regulated has only been partially elucidated. We report that the scaffolding proteins β-arrestins (β-arrs) are important regulators of PTEN. Downstream of receptor-activated RhoA/ROCK signalling, β-arrs activate the lipid phosphatase activi ...[more]

PMID: 21642958

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Project description:The process that partitions the nascent vertebrate central nervous system into forebrain, midbrain, hindbrain, and spinal cord after neural induction is of fundamental interest in developmental biology, and is known to be dependent on Wnt/beta-catenin signaling at multiple steps. Neural induction specifies neural ectoderm with forebrain character that is subsequently posteriorized by graded Wnt signaling: embryological and mutant analyses have shown that progressively higher levels of Wnt signaling induce progressively more posterior fates. However, the mechanistic link between Wnt signaling and the molecular subdivision of the neural ectoderm into distinct domains in the anteroposterior (AP) axis is still not clear. To better understand how Wnt mediates neural AP patterning, we performed a temporal dissection of neural patterning in response to manipulations of Wnt signaling in zebrafish. We show that Wnt-mediated neural patterning in zebrafish can be divided into three phases: (I) a primary AP patterning phase, which occurs during gastrulation, (II) a mes/r1 (mesencephalon-rhombomere 1) specification and refinement phase, which occurs immediately after gastrulation, and (III) a midbrain-hindbrain boundary (MHB) morphogenesis phase, which occurs during segmentation stages. A major outcome of these Wnt signaling phases is the specification of the major compartment divisions of the developing brain: first the MHB, then the diencephalic-mesencephalic boundary (DMB). The specification of these lineage divisions depends upon the dynamic changes of gene transcription in response to Wnt signaling, which we show primarily involves transcriptional repression or indirect activation. We show that otx2b is directly repressed by Wnt signaling during primary AP patterning, but becomes resistant to Wnt-mediated repression during late gastrulation. Also during late gastrulation, Wnt signaling becomes both necessary and sufficient for expression of wnt8b, en2a, and her5 in mes/r1. We suggest that the change in otx2b response to Wnt regulation enables a transition to the mes/r1 phase of Wnt-mediated patterning, as it ensures that Wnts expressed in the midbrain and MHB do not suppress midbrain identity, and consequently reinforce formation of the DMB. These findings integrate important temporal elements into our spatial understanding of Wnt-mediated neural patterning and may serve as an important basis of a better understanding of neural patterning defects that have implications in human health.

Dataset Information

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

Publications

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

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