ArticleMolecular biology of the cell2014
Interaction of Nck1 and PERK phosphorylated at Y⁵⁶¹ negatively modulates PERK activity and PERK regulation of pancreatic β-cell proinsulin content.
Article in Molecular biology of the cell, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- Regulation of trophoblast fusion dysfunction in preeclampsia by the NCK1/EIF3D/PPARG axis.Biological research · 2026Article
- Review
- Signaling plasticity in the integrated stress response.Frontiers in cell and developmental biology · 2023Review
- Review
- Lack of Nck1 protein and Nck-CD3 interaction caused the increment of lipid content in Jurkat T cells.BMC molecular and cell biology · 2022Article
- Activation of farnesoid X receptor suppresses ER stress and inflammationFrontiers in nutrition · 2022Article
- Article
- Nck adaptors at a glance.Journal of cell science · 2021Article
- Normal and defective pathways in biogenesis and maintenance of the insulin storage pool.The Journal of clinical investigation · 2021Review
- Sinner or Saint?: Nck Adaptor Proteins in Vascular Biology.Frontiers in cell and developmental biology · 2021Review
- Peptide-based sequestration of the adaptor protein Nck1 in pancreatic β cells enhances insulin biogenesis and protects against diabetogenic stresses.The Journal of biological chemistry · 2018Article
- Nck2, an unexpected regulator of adipogenesis.Adipocyte · 2017Article
- Unconjugated secondary bile acids activate the unfolded protein response and induce golgi fragmentation via a src-kinase-dependant mechanism.Oncotarget · 2017Article
- Calcineurin β protects brain after injury by activating the unfolded protein response.Neurobiology of disease · 2016Article
- mTORC1 and CK2 coordinate ternary and eIF4F complex assembly.Nature communications · 2016Article
- Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes.Translational research : the journal of laboratory and clinical medicine · 2016Article
- Mcl-1 downregulation leads to the heightened sensitivity exhibited by BCR-ABL positive ALL to induction of energy and ER-stress.Leukemia research · 2015Article
- Robust Endoplasmic Reticulum-Associated Degradation of Rhodopsin Precedes Retinal Degeneration.Molecular neurobiology · 2015Article
- Nck1 depletion induces activation of the PI3K/Akt pathway by attenuating PTP1B protein expression.Cell communication and signaling : CCS · 2014Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
PERK, the PKR-like endoplasmic reticulum (ER) kinase, is an ER transmembrane serine/threonine protein kinase activated during ER stress. In this study, we provide evidence that the Src-homology domain-containing adaptor Nck1 negatively regulates PERK. We show that Nck directly binds to phosphorylated Y(561) in the PERK juxtamembrane domain through its SH2 domain. We demonstrate that mutation of Y(561) to a nonphosphorylatable residue (Y561F) promotes PERK activity, suggesting that PERK phosphorylation at Y(561) (pY(561)PERK) negatively regulates PERK. In agreement, we show that pY(561)PERK delays PERK activation and signaling during ER stress. Compatible with a role for PERK in pancreatic β-cells, we provide strong evidence that Nck1 contributes to PERK regulation of pancreatic β-cell proteostasis. In fact, we demonstrated that down-regulation of Nck1 in mouse insulinoma MIN6 cells results in faster dephosphorylation of pY(561)PERK, which correlates with enhanced PERK activation, increased insulin biosynthesis, and PERK-dependent increase in proinsulin content. Furthermore, we report that pancreatic islets in whole-body Nck1-knockout mice contain more insulin than control littermates. Together our data strongly suggest that Nck1 negatively regulates PERK by interacting with PERK and protecting PERK from being dephosphorylated at its inhibitory site pY(561) and in this way affects pancreatic β-cell proinsulin biogenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.