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Centrosomes are required for proper ?-catenin processing and Wnt response.

ABSTRACT: The Wnt/?-catenin signaling pathway is central to metazoan development and routinely dysregulated in cancer. Wnt/?-catenin signaling initiates transcriptional reprogramming upon stabilization of the transcription factor ?-catenin, which is otherwise posttranslationally processed by a destruction complex and degraded by the proteasome. Since various Wnt signaling components are enriched at centrosomes, we examined the functional contribution of centrosomes to Wnt signaling, ?-catenin regulation, and posttranslational modifications. In HEK293 cells depleted of centrosomes we find that ?-catenin synthesis and degradation rates are unaffected but that the normal accumulation of ?-catenin in response to Wnt signaling is attenuated. This is due to accumulation of a novel high-molecular-weight form of phosphorylated ?-catenin that is constitutively degraded in the absence of Wnt. Wnt signaling operates by inhibiting the destruction complex and thereby reducing destruction complex-phosphorylated ?-catenin, but high-molecular-weight ?-catenin is unexpectedly increased by Wnt signaling. Therefore these studies have identified a pool of ?-catenin effectively shielded from regulation by Wnt. We present a model whereby centrosomes prevent inappropriate ?-catenin modifications that antagonize normal stabilization by Wnt signals.

SUBMITTER: Vora SM

PROVIDER: S-EPMC7525817 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Centrosomes are required for proper β-catenin processing and Wnt response.

Vora Setu M SM Fassler Jan S JS Phillips Bryan T BT

Molecular biology of the cell 20200617 17

The Wnt/β-catenin signaling pathway is central to metazoan development and routinely dysregulated in cancer. Wnt/β-catenin signaling initiates transcriptional reprogramming upon stabilization of the transcription factor β-catenin, which is otherwise posttranslationally processed by a destruction complex and degraded by the proteasome. Since various Wnt signaling components are enriched at centrosomes, we examined the functional contribution of centrosomes to Wnt signaling, β-catenin regulation, ...[more]

PMID: 32583737

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Project description:BackgroundBeta-catenin is an essential mediator of canonical Wnt signaling and a central component of the cadherin-catenin epithelial adhesion complex. Dysregulation of beta-catenin expression has been described in pancreatic neoplasia. Newly published studies have suggested that beta-catenin is critical for normal pancreatic development although these reports reached somewhat different conclusions. In addition, the molecular mechanisms by which loss of beta-catenin affects pancreas development are not well understood. The goals of this study then were; 1] to further investigate the role of beta-catenin in pancreatic development using a conditional knockout approach and 2] to identify possible mechanisms by which loss of beta-catenin disrupts pancreatic development. A Pdx1-cre mouse line was used to delete a floxed beta-catenin allele specifically in the developing pancreas, and embryonic pancreata were studied by immunohistochemistry and microarray analysis.ResultsPdx1-cre floxed beta-catenin animals were viable but demonstrated small body size and shortened median survival. The pancreata from knockout mice were hypoplastic and histologically demonstrated a striking paucity of exocrine pancreas, acinar to duct metaplasia, but generally intact pancreatic islets containing all lineages of endocrine cells. In animals with extensive acinar hypoplasia, putative hepatocyte transdifferention was occasionally observed. Obvious and uniform pancreatic hypoplasia was observed by embryonic day E16.5. Transcriptional profiling of Pdx1-cre floxed beta-catenin embryonic pancreata at E14.5, before there was a morphological phenotype, revealed significant decreases in the beta-catenin target gene N-myc, and the basic HLH transcription factor PTF1, and an increase of several pancreatic zymogens compared to control animals. By E16.5, there was a dramatic loss of exocrine markers and an increase in Hoxb4, which is normally expressed anterior to the pancreas.ConclusionWe conclude that beta-catenin expression is required for development of the exocrine pancreas, but is not required for development of the endocrine compartment. In contrast, beta-catenin/Wnt signaling appears to be critical for proliferation of PTF1+ nascent acinar cells and may also function, in part, to maintain an undifferentiated state in exocrine/acinar cell precursors. Finally, beta-catenin may be required to maintain positional identity of the pancreatic endoderm along the anterior-posterior axis. This data is consistent with the findings of frequent beta-catenin mutations in carcinomas of acinar cell lineage seen in humans.

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Centrosomes are required for proper ?-catenin processing and Wnt response.

Publications

Centrosomes are required for proper β-catenin processing and Wnt response.

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