Altered nociception in Alzheimer disease is associated with striatal-enriched protein tyrosine phosphatase signaling

Lee, Zhung Fu; Huang, Tzu Hsuan; Chen, Shih‐Pin; Cheng, Irene H.

doi:10.1097/j.pain.0000000000002180

Cited by 11 publications

(6 citation statements)

References 61 publications

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“…SHP2 ( PTPN11 ) : enhanced expression in fibroblast-like synoviocytes of patients with rheumatoid arthritis 220 ; inhibition with 11a-1 attenuates disease in K/BxN arthritis 221 and MRL-lpr lupus 101 mouse models.…”

Section: Phosphatase Targets In Tumour Immunotherapy and Autoimmune D...mentioning

confidence: 99%

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

Stanford

Bottini

2023

Nat Rev Drug Discov

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Protein phosphatases act as key regulators of multiple important cellular processes and are attractive therapeutic targets for various diseases. Although extensive effort has been dedicated to phosphatase-targeted drug discovery, early expeditions for competitive phosphatase inhibitors were plagued by druggability issues, leading to the stigmatization of phosphatases as difficult targets. Despite challenges, persistent efforts have led to the identification of several drug-like, non-competitive modulators of some of these enzymes — including SH2 domain-containing protein tyrosine phosphatase 2, protein tyrosine phosphatase 1B, vascular endothelial protein tyrosine phosphatase and protein phosphatase 1 — reigniting interest in therapeutic targeting of phosphatases. Here, we discuss recent progress in phosphatase drug discovery, with emphasis on the development of selective modulators that exhibit biological activity. The roles and regulation of protein phosphatases in immune cells and their potential as powerful targets for immuno-oncology and autoimmunity indications are assessed.

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Section: Phosphatase Targets In Tumour Immunotherapy and Autoimmune D...mentioning

confidence: 99%

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

Stanford

Bottini

2023

Nat Rev Drug Discov

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“… 60 , 66 , 67 , 96 Aβ may be associated with the increased inhibitory modulation in the spinal cord and aberrant activation of striatal enriched protein tyrosine phosphatase signaling in hippocampi. 3 , 40 Synaptic damage is usually found in patients with AD with cognitive defect, as well as the synaptic degeneration in 5×familial Alzheimer disease (FAD) mice. 32 , 88 Spine morphodynamics is proved closely related to changes of F-actin-rich cytoskeleton, which are regulated by Rho-GTPases.…”

Section: Introductionmentioning

confidence: 99%

Altered pain sensitivity in 5×familial Alzheimer disease mice is associated with dendritic spine loss in anterior cingulate cortex pyramidal neurons

Cui

Guo

Wei

et al. 2022

Pain

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Chronic pain is highly prevalent. Individuals with cognitive disorders such as Alzheimer disease are a susceptible population in which pain is frequently difficult to diagnosis. It is still unclear whether the pathological changes in patients with Alzheimer disease will affect pain processing. Here, we leverage animal behavior, neural activity recording, optogenetics, chemogenetics, and Alzheimer disease modeling to examine the contribution of the anterior cingulate cortex (ACC) neurons to pain response. The 53 familial Alzheimer disease mice show alleviated mechanical allodynia which can be regained by the genetic activation of ACC excitatory neurons. Furthermore, the lower peak neuronal excitation, delayed response initiation, as well as the dendritic spine reduction of ACC pyramidal neurons in 53familial Alzheimer disease mice can be mimicked by Rac1 or actin polymerization inhibitor in wild-type (WT) mice. These findings indicate that abnormal of pain sensitivity in Alzheimer disease modeling mice is closely related to the variation of neuronal activity and dendritic spine loss in ACC pyramidal neurons, suggesting the crucial role of dendritic spine density in pain processing.

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“…The STEP protein encoded by the PTPN5 gene can generate two main functional isoforms, a membrane‐associated protein termed STEP 61 and a cytosolic protein termed STEP 46 [ 22 , 23 , 24 ]. In the past decades, scientists have revealed that STEP mainly enriches within the central nervous system (CNS) and involves alterations in synaptic transmission, plasticity, memory formation, and neurological disorders [ 19 , 22 , 25 , 26 , 27 ]. However, whether and how STEP phosphatase contributes to the occurrence and development of tumor‐associated diseases, particularly the influence on the therapeutic effect of chemotherapeutic agents (such as EGFR‐TKIs applied in lung cancer), is still in the puzzle.…”

Section: Introductionmentioning

confidence: 99%

Fbxo45‐mediated NP‐STEP₄₆ degradation via K6‐linked ubiquitination sustains ERK activity in lung cancer

Wang

Cai

et al. 2022

Molecular Oncology

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Lung cancer is one of the most threatening malignant tumors to human health. Epidermal growth factor receptor (EGFR)‐targeted therapy is a common and essential means for the clinical treatment of lung cancer. However, drug resistance has always affected the therapeutic effect and survival rate in non‐small cell lung cancer (NSCLC). Tumor heterogeneity is a significant reason, yielding various drug resistance mechanisms, such as EGFR‐dependent or ‐independent extracellular signal‐regulated kinase 1 and/or 2 (ERK1/2) activation in NSCLC. To examine whether this aberrant activation of ERK1/2 is related to the loss of function of its specific phosphatase, a series of in vitro and in vivo assays were performed. We found that F‐box/SPRY domain‐containing protein 1 (Fbxo45) induces ubiquitination of NP‐STEP46, an active form of striatal‐enriched protein tyrosine phosphatase, with a K6‐linked poly‐ubiquitin chain. This ubiquitination led to proteasome degradation in the nucleus, which then sustains the aberrant level of phosphorylated‐ERK (pERK) and promotes tumor growth of NSCLC. Fbxo45 silencing can significantly inhibit cell proliferation and tumor growth. Moreover, NSCLC cells with silenced Fbxo45 showed great sensitivity to the EGFR tyrosine kinase inhibitor (TKI) afatinib. Here, we first report this critical pERK maintenance mechanism, which might be independent of the upstream kinase activity in NSCLC. We propose that inhibiting Fbxo45 may combat the issue of drug resistance in NSCLC patients, especially combining with EGFR‐TKI therapy.

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Altered nociception in Alzheimer disease is associated with striatal-enriched protein tyrosine phosphatase signaling

Cited by 11 publications

References 61 publications

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

Altered pain sensitivity in 5×familial Alzheimer disease mice is associated with dendritic spine loss in anterior cingulate cortex pyramidal neurons

Fbxo45‐mediated NP‐STEP₄₆ degradation via K6‐linked ubiquitination sustains ERK activity in lung cancer

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Altered nociception in Alzheimer disease is associated with striatal-enriched protein tyrosine phosphatase signaling

Cited by 11 publications

References 61 publications

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

Altered pain sensitivity in 5×familial Alzheimer disease mice is associated with dendritic spine loss in anterior cingulate cortex pyramidal neurons

Fbxo45‐mediated NP‐STEP46 degradation via K6‐linked ubiquitination sustains ERK activity in lung cancer

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Fbxo45‐mediated NP‐STEP₄₆ degradation via K6‐linked ubiquitination sustains ERK activity in lung cancer