ArticleProceedings of the National Academy of Sciences of the United States of America2015
STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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Who cites it
39 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.
- The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.Pharmacology & therapeutics · 2020Pooled it
- Fyn kinase: a key mechanistic regulator and therapeutic target in tauopathy and neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Species-dependent activities of the PINK1-parkin axis.Translational neurodegeneration · 2026Review
- Phosphatase Signaling as a Therapeutic Strategy in Schizophrenia.International journal of molecular sciences · 2026Review
- Article
- Unveiling the hidden dangers: a review of non-apoptotic programmed cell death in anesthetic-induced developmental neurotoxicity.Cell biology and toxicology · 2024Review
- The Role of the Vascular System in Degenerative Diseases: Mechanisms and Implications.International journal of molecular sciences · 2024Review
- Pushed to extremes: distinct effects of high temperature versus pressure on the structure of STEP.Communications biology · 2024Article
- Pushed to extremes: distinct effects of high temperature vs. pressure on the structure of an atypical phosphatase.bioRxiv : the preprint server for biology · 2023Article
- Detection of Cellular Target Engagement for Small-Molecule Modulators of Striatal-Enriched Protein Tyrosine Phosphatase (STEP).Methods in molecular biology (Clifton, N.J.) · 2023Article
- Sevoflurane exposure during the second trimester induces neurotoxicity in offspring rats by hyperactivation of PARP-1.Psychopharmacology · 2022Article
- Fbxo45-mediated NP-STEPMolecular oncology · 2022Article
- Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?Frontiers in cell and developmental biology · 2022Review
- Fyn Kinase Activity and Its Role in Neurodegenerative Disease Pathology: a Potential Universal Target?Molecular neurobiology · 2021Review
- Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP).International journal of molecular sciences · 2021Article
- Pivotal Role of Fyn Kinase in Parkinson's Disease and Levodopa-Induced Dyskinesia: a Novel Therapeutic Target?Molecular neurobiology · 2021Review
- STEP inhibition prevents Aβ-mediated damage in dendritic complexity and spine density in Alzheimer's disease.Experimental brain research · 2021Article
- The Implication of STEP in Synaptic Plasticity and Cognitive Impairments in Alzheimer's Disease and Other Neurological Disorders.Frontiers in cell and developmental biology · 2021Review
- Insight into the Role of the STriatal-Enriched Protein Tyrosine Phosphatase (STEP) in AFrontiers in pharmacology · 2021Article
- The Non-receptor Tyrosine Kinase Pyk2 in Brain Function and Neurological and Psychiatric Diseases.Frontiers in synaptic neuroscience · 2021Review
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Authors and funding
7 authors at 2 institutions in 3 countries.
Funding
Abstract
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The loss of SNc dopaminergic neurons affects the plasticity of striatal neurons and leads to significant motor and cognitive disabilities during the progression of the disease. PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in genetic and sporadic PD. Mutations in PARK2 are a major contributing factor in the early onset of autosomal-recessive juvenile parkinsonism (AR-JP), although the mechanisms by which a disruption in parkin function contributes to the pathophysiology of PD remain unclear. Here we demonstrate that parkin is an E3 ligase for STEP61 (striatal-enriched protein tyrosine phosphatase), a protein tyrosine phosphatase implicated in several neuropsychiatric disorders. In cellular models, parkin ubiquitinates STEP61 and thereby regulates its level through the proteasome system, whereas clinically relevant parkin mutants fail to do so. STEP61 protein levels are elevated on acute down-regulation of parkin or in PARK2 KO rat striatum. Relevant to PD, STEP61 accumulates in the striatum of human sporadic PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. The increase in STEP61 is associated with a decrease in the phosphorylation of its substrate ERK1/2 and the downstream target of ERK1/2, pCREB [phospho-CREB (cAMP response element-binding protein)]. These results indicate that STEP61 is a novel substrate of parkin, although further studies are necessary to determine whether elevated STEP61 levels directly contribute to the pathophysiology of PD.
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