ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
Phosphorylation of HSP27 by protein kinase D is essential for mediating neuroprotection against ischemic neuronal injury.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 95 citations in OpenAlex.
- Remote Ischemic Conditioning in Patients With Acute Ischemic Stroke Ineligible for Recanalization Therapies: A Phase II Trial.Stroke (Hoboken, N.J.) · 2026Article
- Hspb1 inhibits microglial ferroptosis and pro-inflammatory activation to alleviate cerebral ischemia/reperfusion injury in mice.Neural regeneration research · 2026Article
- Down-regulation of neuroprotective protein kinase D in Huntington´s disease.Cell death & disease · 2025Article
- Review
- T817MA attenuates oxidative stress and ER stress via the HSP70-HSP90 pathway after brain ischemiaFrontiers in pharmacology · 2025Article
- Astrocyte-Derived Extracellular Vesicles for Ischemic Stroke: Therapeutic Potential and Prospective.Aging and disease · 2024Review
- Protein kinase D1 - A targetable mediator of pancreatic cancer development.Biochimica et biophysica acta. Molecular cell research · 2024Review
- Salt-induced phosphoproteomic changes in the subfornical organ in rats with chronic kidney disease.Renal failure · 2023Article
- A Novel Needle Mouse Model of Vascular Cognitive Impairment and Dementia.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Protein kinase D2 confers neuroprotection by promoting AKT and CREB activation in ischemic stroke.Neurobiology of disease · 2023Article
- Review
- Impact of Non-Invasive Physical Plasma on Heat Shock Protein Functionality in Eukaryotic Cells.Biomedicines · 2023Article
- FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer.Journal of experimental & clinical cancer research : CR · 2023Article
- Incretin Mimetics Restore the ER-Mitochondrial Axis and Switch Cell Fate Towards Survival in LUHMES Dopaminergic-Like Neurons: Implications for Novel Therapeutic Strategies in Parkinson's Disease.Journal of Parkinson's disease · 2023Article
- The lysophosphatidic acid-regulated signal transduction network in ovarian cancer cells and its role in actomyosin dynamics, cell migration and entosis.Theranostics · 2023Article
- Regulation of Inflammatory Cell Death by Phosphorylation.Frontiers in immunology · 2022Review
- Hypoxia Tolerant Species: The Wisdom of Nature Translated into Targets for Stroke Therapy.International journal of molecular sciences · 2021Review
- The chaperone HSPB1 prepares protein aggregates for resolubilization by HSP70.Scientific reports · 2021Article
- Multifaceted Functions of Protein Kinase D in Pathological Processes and Human Diseases.Biomolecules · 2021Review
- Geranylgeranylacetone attenuates cerebral ischemia-reperfusion injury in rats through the augmentation of HSP 27 phosphorylation: a preliminary study.BMC neuroscience · 2021Article
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
Heat shock protein 27 (HSP27) (or HSPB1) exerts cytoprotection against many cellular insults, including cerebral ischemia. We previously identified apoptosis signal-regulating kinase 1 (ASK1) as a critical downstream target of HSP27 conferring the neuroprotective effects of HSP27 against neuronal ischemia. However, the function of HSP27 is highly influenced by posttranslational modification, with differential cellular effects based on phosphorylation at specific serine residues. The role of phosphorylation in neuronal ischemic neuroprotection is currently unknown. We have created transgenic mice and viral vectors containing HSP27 mutated at three critical serine residues (Ser15, Ser78, and Ser82) to either alanine (HSP27-A, nonphosphorylatable) or aspartate (HSP27-D, phosphomimetic) residues. Under both in vitro and in vivo neuronal ischemic settings, overexpression of wild-type HSP27 (HSP27) and HSP27-D, but not HSP27-A, was neuroprotective and inhibited downstream ASK1 signaling pathways. Consistently, overexpressed HSP27 was phosphorylated by endogenous mechanisms when neurons were under ischemic stress, and single-point mutations identified Ser15 and Ser82 as critical for neuroprotection. Using a panel of inhibitors and gene knockdown approaches, we identified the upstream kinase protein kinase D (PKD) as the primary kinase targeting HSP27 directly for phosphorylation. PKD and HSP27 coimmunoprecipitated, and inhibition or knockdown of PKD abrogated the neuroprotective effects of HSP27 as well as the interaction with and inhibition of ASK1 signaling. Together, these data demonstrate that HSP27 requires PKD-mediated phosphorylation for its suppression of ASK1 cell death signaling and neuroprotection against ischemic injury.
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