Comment on Goldsworthy et al. Haploinsufficiency of the Insulin Receptor in the Presence of a Splice-Site Mutation in <i>Ppp2r2a</i> Results in a Novel Digenic Mouse Model of Type 2 Diabetes. Diabetes 2016;65:1434–1446

Cristóbal, Ion; Madoz‐Gúrpide, Juan; Rojo, Federico; Garcı́a-Foncillas, Jesús

doi:10.2337/db16-0249

Cited by 2 publications

(3 citation statements)

References 9 publications

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“…Several molecular abnormalities are linked to T2DM, in which mutations in important regulatory networks remain substantial (7)(8)(9). Pancreatic β-cell injury and insulin resistance appear to be partially triggered by inflammatory (10), oxidative (11) J o u r n a l P r e -p r o o f and endoplasmic reticulum stress-induced pathways (12), including the mitogenactivated protein kinases (MAPK) signaling cascade.…”

Section: Introductionmentioning

confidence: 99%

Metformin inhibits MAPK signaling and rescues pancreatic aquaporin 7 expression to induce insulin secretion in type 2 diabetes mellitus

Gao

Hou

et al. 2021

Journal of Biological Chemistry

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Section: Introductionmentioning

confidence: 99%

Metformin inhibits MAPK signaling and rescues pancreatic aquaporin 7 expression to induce insulin secretion in type 2 diabetes mellitus

Gao

Hou

et al. 2021

Journal of Biological Chemistry

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“…Together with protein phosphatase 1 (PP1), PP2A is responsible for over 90% of Ser/Thr de-phosphorylation in most cells (Eichhorn et al, 2009). Dysregulated PP2A activity is associated with numerous diseases, including, but not limited to, Alzheimer's disease, various cancers, diabetes, cardiac disease, asthma, inflammation and auto-immune conditions (Calin et al, 2000;Takagi et al, 2000;Suzuki and Takahashi, 2003;Neviani et al, 2005;Kowluru and Matti, 2012;Collison et al, 2013;Crispin et al, 2013;Sontag and Sontag, 2014;Lei et al, 2015;Goldsworthy et al, 2016;Ross et al, 2017;Refaey et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…A recent ENU-induced mutagenesis study reported a splice-site mutation in Ppp2r2a resulting in reduced PP2A-B55α expression. Generation of double heterozygous mice for this Ppp2r2a mutation and a null allele of the gene encoding the insulin receptor, resulted in a diabetic phenotype characterized by hyperglycemia, hyperinsulinemia, impaired glucose tolerance, and glycosuria (Goldsworthy et al, 2016), suggesting PP2A-B55α may play a role in metabolism and insulin signaling.…”

Section: Introductionmentioning

confidence: 99%

Ppp2r2a Knockout Mice Reveal That Protein Phosphatase 2A Regulatory Subunit, PP2A-B55α, Is an Essential Regulator of Neuronal and Epidermal Embryonic Development

Panicker

Coutman

Lawlor-O’Neill

et al. 2020

Front. Cell Dev. Biol.

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The serine/threonine protein phosphatase 2A (PP2A) is a master regulator of the complex cellular signaling that occurs during all stages of mammalian development. PP2A is composed of a catalytic, a structural, and regulatory subunit, for which there are multiple isoforms. The association of specific regulatory subunits determines substrate specificity and localization of phosphatase activity, however, the precise role of each regulatory subunit in development is not known. Here we report the generation of the first knockout mouse for the Ppp2r2a gene, encoding the PP2A-B55α regulatory subunit, using CRISPR/Cas9. Heterozygous animals developed and grew as normal, however, homozygous knockout mice were not viable. Analysis of embryos at different developmental stages found a normal Mendelian ratio of Ppp2r2a −/− embryos at embryonic day (E) 10.5 (25%), but reduced Ppp2r2a −/− embryos at E14.5 (18%), and further reduced at E18.5 (10%). No live Ppp2r2a −/− pups were observed at birth. Ppp2r2a −/− embryos were significantly smaller than wild-type or heterozygous littermates and displayed a variety of neural defects such as exencephaly, spina bifida, and cranial vault collapse, as well as syndactyly and severe epidermal defects; all processes driven by growth and differentiation of the ectoderm. Ppp2r2a −/− embryos had incomplete epidermal barrier acquisition, associated with thin, poorly differentiated stratified epithelium with weak attachment to the underlying dermis. The basal keratinocytes in Ppp2r2a −/− embryos were highly disorganized, with reduced immunolabeling of integrins and basement membrane proteins, suggesting impaired focal adhesion and hemidesmosome assembly. The spinous and granular layers were thinner in the Ppp2r2a −/− embryos, with aberrant expression of adherens and tight junction associated proteins. The overlying stratum corneum was either absent or incomplete. Thus PP2A-B55α is an essential regulator of epidermal stratification, and is essential for ectodermal development during embryogenesis.

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Comment on Goldsworthy et al. Haploinsufficiency of the Insulin Receptor in the Presence of a Splice-Site Mutation in Ppp2r2a Results in a Novel Digenic Mouse Model of Type 2 Diabetes. Diabetes 2016;65:1434–1446

Cited by 2 publications

References 9 publications

Metformin inhibits MAPK signaling and rescues pancreatic aquaporin 7 expression to induce insulin secretion in type 2 diabetes mellitus

Metformin inhibits MAPK signaling and rescues pancreatic aquaporin 7 expression to induce insulin secretion in type 2 diabetes mellitus

Ppp2r2a Knockout Mice Reveal That Protein Phosphatase 2A Regulatory Subunit, PP2A-B55α, Is an Essential Regulator of Neuronal and Epidermal Embryonic Development

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