Regulation of the AMPK-related protein kinases by ubiquitination

2008 ◽  
Vol 411 (2) ◽  
pp. e9-e10 ◽  
Author(s):  
David M. Thomson ◽  
Marc D. H. Hansen ◽  
William W. Winder
Keyword(s):  
Deubiquitinating Enzyme ◽  
Polyubiquitin Chains ◽  
Kinase Substrate ◽  
Biochemical Journal ◽  
Substrate Level ◽  
Amp Activated Protein Kinase ◽  
And Control

How can a constitutively active ‘master’ kinase with numerous downstream targets preferentially phosphorylate one or more of these without influencing all simultaneously? How might such a system be switched off? The characterization of the role of deubiquitination in regulating the phosphorylation and activation of AMPK (AMP-activated protein kinase)-related kinases by LKB1 suggests a novel and interesting mechanism for conferring signal transduction specificity and control at the kinase substrate level. In this issue of the Biochemical Journal, Al-Hakim et al. show that the AMPK-related kinases NUAK1 (AMPK-related kinase 5) and MARK4 (microtubule-affinity-regulating kinase 4) are polyubiquitinated in vivo and that they serve as substrates of the deubiquitinating enzyme USP9X; furthermore, the first evidence is provided for regulation of AMPK-related kinase family members mediated via unusual Lys29/Lys33 polyubiquitin chains, rather than the more common Lys48/Lys63 linkages.

scholarly journals Characterization of OTUB1 activation and inhibition by different E2 enzymes

2019 ◽  
Author(s):  
Lauren T. Que ◽  
Marie E. Morrow ◽  
Cynthia Wolberger
Keyword(s):  
Deubiquitinating Enzyme ◽  
Polyubiquitin Chains ◽  
Kinetics And Thermodynamics ◽  
Conjugating Enzymes ◽  
E2 Enzymes ◽  
Ubiquitin Conjugating Enzymes ◽  
Stimulation Of

AbstractOTUB1 is a highly expressed cysteine protease that specifically cleaves K48-linked polyubiquitin chains. This unique deubiquitinating enzyme (DUB) can bind to a subset of E2 ubiquitin conjugating enzymes, forming complexes in which the two enzymes can regulate one another’s activity. OTUB1 can non-catalytically suppress the ubiquitin conjugating activity of its E2 partners by sequestering the charged E2~Ub thioester and preventing ubiquitin transfer. The same E2 enzymes, when uncharged, can stimulate the DUB activity of OTUB1 in vitro, although the importance of OTUB1 stimulation in vivo remains unclear. In order to assess the potential balance between these activities that might occur in cells, we characterized the kinetics and thermodynamics governing the formation and activity of OTUB1:E2 complexes. We show that both stimulation of OTUB1 by E2 enzymes and noncatalytic inhibition of E2 enzymes by OTUB1 occur at physiologically relevant concentrations of both partners. Whereas E2 partners differ in their ability to stimulate OTUB1 activity, we find that this variability is not correlated with the affinity of each E2 for OTUB1. In addition to UBE2N and the UBE2D isoforms, we find that OTUB1 inhibits polyubiquitination activity of all three UBE2E enzymes, UBE2E1, UBE2E2, and UBE2E3. Interestingly, although OTUB1 also inhibits the autoubiquitination activity of UBE2E1 and UBE2E2, it is unable to suppress autoubiquitination by UBE2E3.

Control of AMPK-related kinases by USP9X and atypical Lys29/Lys33-linked polyubiquitin chains

2008 ◽  
Vol 411 (2) ◽  
pp. 249-260 ◽  
Author(s):  
Abdallah K. Al-Hakim ◽  
Anna Zagorska ◽  
Louise Chapman ◽  
Maria Deak ◽  
Mark Peggie ◽  
...  
Keyword(s):  
Topological Analysis ◽  
Deubiquitinating Enzyme ◽  
Wild Type ◽  
Polyubiquitin Chains ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Amp Activated Protein Kinase ◽  
Loop Residue ◽  
In Cells

AMPK (AMP-activated protein kinase)-related kinases regulate cell polarity as well as proliferation and are activated by the LKB1-tumour suppressor kinase. In the present study we demonstrate that the AMPK-related kinases, NUAK1 (AMPK-related kinase 5) and MARK4 (microtubule-affinity-regulating kinase 4), are polyubiquitinated in vivo and interact with the deubiquitinating enzyme USP9X (ubiquitin specific protease-9). Knockdown of USP9X increased polyubiquitination of NUAK1 and MARK4, whereas overexpression of USP9X inhibited ubiquitination. USP9X, catalysed the removal of polyubiquitin chains from wild-type NUAK1, but not from a non-USP9X-binding mutant. Topological analysis revealed that ubiquitin monomers attached to NUAK1 and MARK4 are linked by Lys29 and/or Lys33 rather than the more common Lys48/Lys63. We find that AMPK and other AMPK-related kinases are also polyubiquitinated in cells. We identified non-USP9X-binding mutants of NUAK1 and MARK4 and find that these are hyper-ubiquitinated and not phosphorylated at their T-loop residue targeted by LKB1 when expressed in cells, suggesting that polyubiquitination may inhibit these enzymes. The results of the present study demonstrate that NUAK1 and MARK4 are substrates of USP9X and provide the first evidence that AMPK family kinases are regulated by unusual Lys29/Lys33-linked polyubiquitin chains.

scholarly journals Netrin-1 in Atherosclerosis: Relationship between Human Macrophage Intracellular Levels and In Vivo Plaque Morphology

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 168
Author(s):  
Susanna Fiorelli ◽  
Nicola Cosentino ◽  
Benedetta Porro ◽  
Franco Fabbiocchi ◽  
Giampaolo Niccoli ◽  
...  
Keyword(s):  
Progressive Increase ◽  
Human Macrophage ◽  
Plaque Morphology ◽  
Artery Disease ◽  
Atherosclerotic Process ◽  
And Function ◽  
And Control ◽  
Macrophage Accumulation

Netrin-1 is a laminin-like protein that plays a pivotal role in cell migration and, according to the site of its release, exerts both pro and anti-atherosclerotic functions. Macrophages, key cells in atherosclerosis, are heterogeneous in morphology and function and different subpopulations may support plaque progression, stabilization, and/or regression. Netrin-1 was evaluated in plasma and, together with its receptor UNC5b, in both spindle and round monocyte-derived macrophages (MDMs) morphotypes from coronary artery disease (CAD) patients and control subjects. In CAD patients, plaque features were detected in vivo by optical coherence tomography. CAD patients had lower plasma Netrin-1 levels and a higher MDMs expression of both protein and its receptor compared to controls. Specifically, a progressive increase in Netrin-1 and UNC5b was evidenced going from controls to stable angina (SA) and acute myocardial infarction (AMI) patients. Of note, spindle MDMs of AMI showed a marked increase of both Netrin-1 and its receptor compared to spindle MDMs of controls. UNC5b expression is always higher in spindle compared to round MDMs, regardless of the subgroup. Finally, CAD patients with higher intracellular Netrin-1 levels showed greater intraplaque macrophage accumulation in vivo. Our findings support the role of Netrin-1 and UNC5b in the atherosclerotic process.

Toward heterogeneity in feedforward network with synaptic delays based on FitzHugh–Nagumo model

2018 ◽  
Vol 32 (01) ◽  
pp. 1750274 ◽  
Author(s):  
Ying-Mei Qin ◽  
Cong Men ◽  
Jia Zhao ◽  
Chun-Xiao Han ◽  
Yan-Qiu Che
Keyword(s):  
Neuronal Excitability ◽  
Temporal Coding ◽  
Feedforward Network ◽  
Firing Patterns ◽  
In Vivo Experiments ◽  
Connection Probability ◽  
Rate Coding

We focus on the role of heterogeneity on the propagation of firing patterns in feedforward network (FFN). Effects of heterogeneities both in parameters of neuronal excitability and synaptic delays are investigated systematically. Neuronal heterogeneity is found to modulate firing rates and spiking regularity by changing the excitability of the network. Synaptic delays are strongly related with desynchronized and synchronized firing patterns of the FFN, which indicate that synaptic delays may play a significant role in bridging rate coding and temporal coding. Furthermore, quasi-coherence resonance (quasi-CR) phenomenon is observed in the parameter domain of connection probability and delay-heterogeneity. All these phenomena above enable a detailed characterization of neuronal heterogeneity in FFN, which may play an indispensable role in reproducing the important properties of in vivo experiments.

scholarly journals Intracellular and Computational Characterization of the Intracortical Inhibitory Control of Synchronized Thalamic Inputs In Vivo

1997 ◽  
Vol 78 (1) ◽  
pp. 335-350 ◽  
Author(s):  
Diego Contreras ◽  
Alain Destexhe ◽  
Mircea Steriade
Keyword(s):  
Inhibitory Control ◽  
Computational Models ◽  
Pyramidal Cells ◽  
Excitatory Postsynaptic Potential ◽  
Thalamic Stimulation ◽  
Postsynaptic Potential ◽  
Spike Wave

Contreras, Diego, Alain Destexhe, and Mircea Steriade. Intracellular and computational characterization of the intracortical inhibitory control of synchronized thalamic inputs in vivo. J. Neurophysiol. 78: 335–350, 1997. We investigated the presence and role of local inhibitory cortical control over synchronized thalamic inputs during spindle oscillations (7–14 Hz) by combining intracellular recordings of pyramidal cells in barbiturate-anesthetized cats and computational models. The recordings showed that 1) similar excitatory postsynaptic potential (EPSP)/inhibitory postsynaptic potential (IPSP) sequences occurred either during spindles or following thalamic stimulation; 2) reversed IPSPs with chloride-filled pipettes transformed spindle-related EPSP/IPSP sequences into robust bursts with spike inactivation, resembling paroxysmal depolarizing shifts during seizures; and 3) dual simultaneous impalements showed that inhibition associated with synchronized thalamic inputs is local. Computational models were based on reconstructed pyramidal cells constrained by recordings from the same cells. These models showed that the transformation of EPSP/IPSP sequences into fully developed spike bursts critically needs a relatively high density of inhibitory currents in the soma and proximal dendrites. In addition, models predict significant Ca2+ transients in dendrites due to synchronized thalamic inputs. We conclude that synchronized thalamic inputs are subject to strong inhibitory control within the cortex and propose that 1) local impairment of inhibition contributes to the transformation of spindles into spike-wave-type discharges, and 2) spindle-related inputs trigger Ca2+ events in cortical dendrites that may subserve plasticity phenomena during sleep.

scholarly journals The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 347 ◽  
Author(s):  
Miguel Fontecha-Barriuso ◽  
Diego Martin-Sanchez ◽  
Julio Manuel Martinez-Moreno ◽  
Maria Monsalve ◽  
Adrian Mario Ramos ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Pde Inhibitors ◽  
Its Gene ◽  
Attractive Therapeutic Target ◽  
Amp Activated Protein Kinase

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.

In vivo chemotactic properties and spatial expression of PDGF in developing mesenteric microvascular networks

2001 ◽  
Vol 280 (5) ◽  
pp. H2116-H2125 ◽  
Author(s):  
Peter J. Zeller ◽  
Thomas C. Skalak ◽  
Ana M. Ponce ◽  
Richard J. Price
Keyword(s):  
Smooth Muscle ◽  
Paracrine Signaling ◽  
Microvascular Networks ◽  
Cell Recruitment ◽  
Perivascular Cell ◽  
Fibroblast Migration ◽  
Pdgf Signaling ◽  
And Control

The recruitment of perivascular cells to developing microvessels is a key component of microvessel assembly. Whereas platelet-derived growth factor (PDGF) signaling is critical for this process during embryonic development, its role from the postnatal stages through adulthood remains unclear. We investigated the potential role of PDGF signaling during microvessel assembly by measuring in vivo the migration of labeled fibroblasts to PDGF in mesenteric connective tissue and by examining PDGF-B and PDGF receptor-β (PGDFR-β) expression in microvascular networks during normal maturation. PDGF-B homodimer (PDGF-BB; 30 ng/ml) application elicited a significant ( P < 0.05) increase (7.8 ± 4.1 cells) in labeled fibroblasts within 100 μm of the source micropipette after 2 h. PDGF-A homodimer (30 ng/ml) application and control solution did not elicit directed migration. PDGF-B was expressed in microvessel endothelium and smooth muscle, whereas PDGFR-β was expressed in endothelium, smooth muscle, and interstitial fibroblasts. Given that PDGF-BB elicits fibroblast migration in the mesentery and that PDGF-B and PDGFR-β are expressed in a pattern that indicates paracrine signaling from microvessels to the interstitium, the results are consistent with a role for PDGF-B in perivascular cell recruitment to microvessels.

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