Abstract
STEP (STriatal-Enriched Protein Tyrosine Phosphatase) is a brain-specific phosphatase that plays an important role in controlling signaling molecules involved in neuronal activity and synaptic development. The striatum is the main location of the STEP enzyme. An imbalance in STEP61 activity is a risk factor for Alzheimer’s disease (AD). It can contribute to the development of numerous neuropsychiatric diseases, including Parkinson’s disease (PD), schizophrenia, fragile X syndrome (FXS), Huntington’s disease (HD), alcoholism, cerebral ischemia, and stress-related diseases. The molecular structure, chemistry, and molecular mechanisms associated with STEP61’s two major substrates, Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAr) and N-methyl-d-aspartate receptors (NMDARs), are crucial in understanding the relationship between STEP61 and associated illnesses. STEP’s interactions with its substrate proteins can alter the pathways of long-term potentiation and long-term depression. Therefore, understanding the role of STEP61 in neurological illnesses, particularly Alzheimer’s disease-associated dementia, can provide valuable insights for possible therapeutic interventions. This review provides valuable insights into the molecular structure, chemistry, and molecular mechanisms associated with STEP61. This brain-specific phosphatase controls signaling molecules involved in neuronal activity and synaptic development. This review can aid researchers in gaining deep insights into the complex functions of STEP61.
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Data Availability
The data used in this review article are primarily derived from online available sources, including academic journals, books and reputable online databases. The specific datasets and studies referenced in this review are appropriately cited within the text. Supplementary data were not utilized in the analysis. Further details regarding the sources of data can be found in the Material and Methods section of this article.
Abbreviations
- AD:
-
Alzheimer’s disease
- AMPAr:
-
Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor
- APP:
-
Amyloid precursor protein
- Aβ:
-
Amyloid beta
- CNS:
-
Central nervous system
- CSF:
-
Cerebrospinal fluid
- Cyclic AMP:
-
Cyclic adenosine mono phosphate
- DARPP-32:
-
Dopamine- and camp-regulated neuronal phosphoprotein
- DR1:
-
Dopamine receptor1
- EGF:
-
Epidermal growth factor
- ERK1/2:
-
Extracellular signal‑regulated protein kinase
- FMR1:
-
Fragile X mental retardation protein
- FSH:
-
Follicle-stimulating hormone
- FXS:
-
Fragile X syndrome
- Fyn:
-
Proto-oncogene tyrosine-protein kinase
- Glua1/2/3/4:
-
GRIA2
- Glun2b:
-
GRIN2B
- HD:
-
Huntington’s disease
- IL-1B:
-
Interleukin 1 beta
- KIM:
-
Kinase interacting motif domain
- KISS:
-
Kinase specificity sequence domain
- LTD:
-
Long-term depression
- LTP:
-
Long-term potentiation
- MAPK1/3/11/12/13/14:
-
Mitogen-activated protein kinase
- Mhtt:
-
Mutant huntington
- NCBI:
-
National Center for Biotechnology Information
- NMDAr:
-
N-Methyl-d-aspartate receptor
- NRG1:
-
Neuregulin 1
- P38:
-
A group of mitogen-activated protein kinases
- PD:
-
Parkinson’s disease
- PEST:
-
Proline, glutamic acid, serine, threonine
- PKA:
-
Protein kinase A
- PP1:
-
Protein phosphatase 1
- PPIs:
-
Protein–protein interactions
- PPP1R1B:
-
Protein phosphatase 1 regulatory subunit 1B
- PSD-95:
-
Post-synaptic density protein 95
- PTK2B:
-
Protein tyrosine kinase 2beta
- PTP:
-
Phosphatase domain
- PTP1B:
-
Protein tyrosine phosphatase 1B
- PTPN5:
-
Tyrosine-protein phosphatase non-receptor type 5
- Pyk2:
-
Proline-rich tyrosine kinase 2
- Q/R Editing:
-
Replacement of amino acid glutamine by arginine
- SHP2:
-
Src homology region 2 containing protein tyrosine phosphatase 2
- STEP61:
-
STriatal-Enriched protein tyrosine Phosphatase
- STRING (string-db.org):
-
String interactome database
- SZ:
-
Schizophrenia
- Tnfα:
-
Tumor necrosis factor Α
- UPS:
-
Ubiquitin–proteasome system
- WPD:
-
Tryptophan, proline, and aspartic acid loop
- α7nachrs:
-
Alpha7 nicotinic acetylcholine receptor
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This work was supported by an Indo-Hungary Grant received by Prof. Sadhana Sathaye from the Department of Pharmaceutical Sciences and Technology.
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All authors contributed to the study’s design, while PVB and RDD performed data collection and literature review. PVB prepared the first draft of the manuscript, and all authors provided feedback on previous versions. All authors read and approved the final version of the manuscript.
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Bagwe, P.V., Deshpande, R.D., Juhasz, G. et al. Uncovering the Significance of STEP61 in Alzheimer’s Disease: Structure, Substrates, and Interactome. Cell Mol Neurobiol 43, 3099–3113 (2023). https://doi.org/10.1007/s10571-023-01364-2
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DOI: https://doi.org/10.1007/s10571-023-01364-2