Molecular mechanism of <scp>ERK</scp> dephosphorylation by striatal‐enriched protein tyrosine phosphatase

Li, Rong; Xie, Di; Dong, Jun; Li, Hui; Li, Kang Shuai; Su, Jing; Chen, Lai Zhong; Xu, Yonghui; Wang, Hong Mei; Gong, Zheng; Cui, Guo Ying; Yu, Xiao; Wang, Kai; Yao, Wei; Xin, Tao; Li, Min Yong; Xiao, Kun; An, Xiao Fei; Huo, Yuqing; Xu, Zhi; Sun, Jin Peng; Pang, Qi

doi:10.1111/jnc.12463

Cited by 31 publications

(40 citation statements)

References 51 publications

(116 reference statements)

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“…Protein phosphatases can achieve selectivity by docking with specific sites on their substrates (Li et al, 2014; Ragusa et al, 2010). Interestingly, the capacity of the SH2 domain of Lck to interact with CD45 has been previously reported (Ng et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45

et al. 2017

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SUMMARY The Src Family kinase Lck sets a critical threshold for T cell activation because it phosphorylates the TCR complex and the Zap70 kinase. How a T cell controls the abundance of active Lck molecules remains poorly understood. We have identified an unappreciated role for a phosphosite, Y192, within the Lck SH2 domain which profoundly affects the amount of active Lck in cells. Notably, mutation of Y192 blocks critical TCR proximal signaling events and impairs thymocyte development in retrogenic mice. We determined that these defects are caused by hyperphosphorylation of the inhibitory C-terminal tail of Lck. Our findings reveal that modification of Y192 inhibits the ability of CD45 to associate with Lck in cells and dephosphorylate the C-terminal tail of Lck which prevents its adoption of an active open conformation. These results suggest a negative feedback loop which responds to signaling events that tune active Lck amounts and TCR sensitivity.

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Section: Discussionmentioning

confidence: 99%

A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45

et al. 2017

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“…Hydrophobic residues are important in controlling protein activity by regulating phosphorylation as indicated by dephosphorylation of tyrosine residue in ERK [90,91]. It is therefore reasonable to assume that the presence of highly conserved hydrophobic regions in DPMS may play an intricate role for its function [92,93].…”

Section: Future Directionmentioning

confidence: 99%

Dolichol phosphate mannose synthase: a Glycosyltransferase with Unity in molecular diversities

et al. 2017

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N-glycans provide structural and functional stability to asparagine-linked (N-linked) glycoprotein, and add flexibility. Glycan biosynthesis is elaborative, multi-compartmental and involves many glycosyltransferases. Failure to assemble N-glycans leads to phenotypic changes developing infection, cancer, congenital disorders of glycosylation (CDGs) among others. Biosynthesis of N-glycans begins at the endoplasmic reticulum (ER) with the assembly of dolichol-linked tetra-decasaccharide (Glc3Man9GlcNAc2-PP-Dol) where dolichol phosphate mannose synthase (DPMS) plays a central role. DPMS is also essential for GPI anchor biosynthesis as well as for O- and C-mannosylation of proteins in yeast and in mammalian cells. DPMS has been purified from several sources and its gene has been cloned from 39 species (e.g., from protozoan parasite to human). It is an inverting GT-A folded enzyme and classified as GT2 by CAZy (carbohydrate active enZyme; http://www.cazy.org). The sequence alignment detects the presence of a metal binding DAD signature in DPMS from all 39 species but finds cAMP-dependent protein phosphorylation motif (PKA motif) in only 38 species. DPMS also has hydrophobic region(s). Hydropathy analysis of amino acid sequences from bovine, human, S. crevisiae and A. thaliana DPMS show PKA motif is present between the hydrophobic domains. The location of PKA motif as well as the hydrophobic domain(s) in the DPMS sequence vary from species to species. For example, the domain(s) could be located at the center or more towards the C-terminus. Irrespective of their catalytic similarity, the DNA sequence, the amino acid identity, and the lack of a stretch of hydrophobic amino acid residues at the C-terminus, DPMS is still classified as Type I and Type II enzyme. Because of an apparent bio-sensing ability, extracellular signaling and microenvironment regulate DPMS catalytic activity. In this review, we highlight some important features and the molecular diversities of DPMS.

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“…The discovery and administration of a potent and specific STEP inhibitor, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153), to 6-month-old 3xTg AD mice reversed the cognitive deficits in these mice (Xu et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

STEP inhibition prevents Aβ-mediated damage in dendritic complexity and spine density in Alzheimer’s disease.

Chatterjee¹,

Kwon²,

Benedict³

et al. 2020

Preprint

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Loss of dendritic spines and decline of cognitive function are hallmarks of patients with Alzheimer's disease (AD). Previous studies have shown that AD pathophysiology involves increased expression of a central nervous system-enriched protein tyrosine phosphatase called STEP (STriatal-Enriched protein tyrosine Phosphatase). STEP opposes the development of synaptic strengthening by dephosphorylating substrates, including GluN2B, Pyk2 and ERK1/2. Genetic reduction of STEP as well as pharmacological inhibition of STEP improves cognitive function and hippocampal memory in the 3xTg AD mouse model. Here, we show that the improved cognitive function is accompanied by an increase in synaptic connectivity in cell cultures as well as in the triple transgenic AD mouse model, further highlighting the potential of STEP inhibitors as a therapeutic agent. Abbreviations STEP = STriatal-Enriched protein tyrosine Phosphatase AD = Alzheimer's disease 3xTg = triple transgenic mouse model CM = conditioned medium CNS = central nervous system ANOVA = analysis of variance Aβ = beta amyloid GluN2B = glutamate ionotropic receptor NMDA type subunit 2B GluA2 = glutamate ionotropic receptor AMPA type subunit 2 Pyk2 = protein tyrosine kinase 2 ERK1/2 = extracellular signal-regulated kinase-1 SPIN90 = SH3 protein interacting with Nck, 90 kDa WT = wild-type

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Molecular mechanism of ERK dephosphorylation by striatal‐enriched protein tyrosine phosphatase

Cited by 31 publications

References 51 publications

A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45

A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45

Dolichol phosphate mannose synthase: a Glycosyltransferase with Unity in molecular diversities

STEP inhibition prevents Aβ-mediated damage in dendritic complexity and spine density in Alzheimer’s disease.

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