Multisite Phosphoregulation of Cdc25 Activity Refines the Mitotic Entrance
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A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Tunable Ultrasensitivity: Functional Decoupling and Biological Insights Guanyu Wang & Mengshi Zhang
www.nature.com/scientificreports OPEN Tunable ultrasensitivity: functional decoupling and biological insights Guanyu Wang & Mengshi Zhang Sensitivity has become a basic concept in biology, but much less is known about its tuning, probably Received: 21 October 2015 because allosteric cooperativity, the best known mechanism of sensitivity, is determined by rigid Accepted: 30 December 2015 conformations of interacting molecules and is thus difficult to tune. Reversible covalent modification Published: 05 February 2016 (RCM), owing to its systems-level ingenuity, can generate concentration based, tunable sensitivity. Using a mathematical model of regulated RCM, we find sensitivity tuning can be decomposed into two orthogonal modes, which provide great insights into vital biological processes such as tissue development and cell cycle progression. We find that decoupling of the two modes of sensitivity tuning is critical to fidelity of cell fate decision; the decoupling is thus important in development. The decomposition also allows us to solve the ‘wasteful degradation conundrum’ in budding yeast cell cycle checkpoint, which further leads to discovery of a subtle but essential difference between positive feedback and double negative feedback. The latter guarantees revocability of stress-induced cell cycle arrest; while the former does not. By studying concentration conditions in the system, we extend applicability of ultrasensitivity and explain the ubiquity of reversible covalent modification. Sensitivity is important in biology—a cell often needs to make clear-cut decisions such as whether to commit apoptosis or which cell type to become. The best known mechanism of sensitivity is cooperative binding of substrate with enzyme that has more than one binding site. -
Non-Essential Sites Improve Phosphorylation Switch
Non-Essential Sites Improve Phosphorylation Switch Liming Wang, Qing Nie, and German Enciso* Department of Mathematics Center for Mathematical and Complex Biological Systems Center for Complex Biological Systems University of California Irvine, CA 92697 *Corresponding author: [email protected] Running title: non-essential sites improve switch Keywords: multi-site phosphorylation, ultrasensitivity, Hill coefficient, Sic1 Subject of Categories: Signal Transduction Total character count: ~ 22,600 Abstract Multisite phosphorylation is a common form of post-translational protein regulation which has been used to increase the switch-like behavior of the protein response to increasing kinase concentrations. In this paper, we show that phosphorylation sites that are not necessary for protein activation can strongly enhance the switch-like response. In the case of unordered phosphorylation, this holds when a sufficient amount of sites are phosphorylated regardless of their exact position, as occurs in bulk electrostatic activation. We obtained analytic estimates for the Hill coefficient of the switch-like response, and we observed that a trade-off exists between the switch and the kinase threshold for activation. This finding suggests a possible evolutionary mechanism for the relatively large numbers of phosphorylation sites found in various proteins. Introduction Protein phosphorylation is a ubiquitous form of post-translational modification. Since covalently bound phosphate groups are strongly hydrophilic and negatively charged, they can activate or inhibit a protein by changing its conformation or the way it interacts with other proteins. This is a key element of countless molecular systems including many forms of signal transduction, the regulation of the cell cycle and protein degradation. Multiple phosphorylations are often observed on the same protein; for instance, the epidermal growth factor receptor (EGFR) protein becomes activated when it is phosphorylated at multiple tyrosine residues by another EGFR (Alberts, 2002). -
Review Article PTEN Gene: a Model for Genetic Diseases in Dermatology
The Scientific World Journal Volume 2012, Article ID 252457, 8 pages The cientificWorldJOURNAL doi:10.1100/2012/252457 Review Article PTEN Gene: A Model for Genetic Diseases in Dermatology Corrado Romano1 and Carmelo Schepis2 1 Unit of Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, 94018 Troina, Italy 2 Unit of Dermatology, I.R.C.C.S. Associazione Oasi Maria Santissima, 94018 Troina, Italy Correspondence should be addressed to Carmelo Schepis, [email protected] Received 19 October 2011; Accepted 4 January 2012 Academic Editors: G. Vecchio and H. Zitzelsberger Copyright © 2012 C. Romano and C. Schepis. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PTEN gene is considered one of the most mutated tumor suppressor genes in human cancer, and it’s likely to become the first one in the near future. Since 1997, its involvement in tumor suppression has smoothly increased, up to the current importance. Germline mutations of PTEN cause the PTEN hamartoma tumor syndrome (PHTS), which include the past-called Cowden, Bannayan- Riley-Ruvalcaba, Proteus, Proteus-like, and Lhermitte-Duclos syndromes. Somatic mutations of PTEN have been observed in glioblastoma, prostate cancer, and brest cancer cell lines, quoting only the first tissues where the involvement has been proven. The negative regulation of cell interactions with the extracellular matrix could be the way PTEN phosphatase acts as a tumor suppressor. PTEN gene plays an essential role in human development. A recent model sees PTEN function as a stepwise gradation, which can be impaired not only by heterozygous mutations and homozygous losses, but also by other molecular mechanisms, such as transcriptional regression, epigenetic silencing, regulation by microRNAs, posttranslational modification, and aberrant localization. -
Multisite Protein Phosphorylation Makes a Good Threshold but Can Be a Poor Switch
Multisite protein phosphorylation makes a good threshold but can be a poor switch Jeremy Gunawardena* Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115 Communicated by Marc W. Kirschner, Harvard Medical School, Boston, MA, August 23, 2005 (received for review March 7, 2005) Phosphorylation and dephosphorylation play a fundamental role an additional mechanism for creating ultrasensitivity. Catalytic in eukaryotic signaling. Some 30% of proteins are phosphorylated activity is distributive if at most one modification (phosphory- at any time, many on multiple sites, raising the question of how the lation or dephosphorylation) takes place before enzyme and cellular phosphorylation state is regulated. Previous work for one substrate molecules part company. It is processive if two or more and two phosphorylation sites has revealed mechanisms, such as modifications take place during a single encounter. For n ϭ 2, distributive phosphorylation, for switch-like regulation of maxi- Huang and Ferrell (5) showed that distributive P&D causes the mally phosphorylated phosphoforms. These insights have led to steady state proportion of doubly phosphorylated substrate to the influential view that more phosphorylation sites leads to depend ultrasensitively on kinase concentration. In vitro exper- steeper switching, as proposed for substrates like cyclin E and the iments showed that Mek phosphorylation of Erk2 was distrib- cyclin-dependent kinase inhibitor Sic1. An analytical study of the utive (6, 7), and later work found the same for the mitogen- ordered distributive case reveals a more complex story. Multisite activated protein kinase phosphatase MKP3 (8). Ultrasensitivity phosphorylation creates an efficient threshold: The proportion of in the mitogen-activated protein kinase cascade is thought to maximally phosphorylated substrate is maintained close to 0 when underlie the all-or-none maturation of Xenopus oocytes (9). -
An Ultrasensitive Ca Calmodulin-Dependent Protein Kinase II–Protein Phosphatase 1 Switch Facilitates Specificity in Postsynapt
An ultrasensitive Ca2؉͞calmodulin-dependent protein kinase II–protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling J. Michael Bradshaw*†‡, Yoshi Kubota*, Tobias Meyer†, and Howard Schulman* Departments of *Neurobiology and †Molecular Pharmacology, Stanford University School of Medicine, Stanford, CA 94305 Edited by Roger A. Nicoll, University of California, San Francisco, CA, and approved July 21, 2003 (received for review May 7, 2003) The strength of hippocampal synapses can be persistently in- hence would provide a distinct Ca2ϩ activation region for creased by signals that activate Ca2؉͞calmodulin-dependent pro- CaMKII compared with other Ca2ϩ-activated enzymes at the tein kinase II (CaMKII). This CaMKII-dependent long-term potenti- synapse. In fact, it has been hypothesized that the signaling ation is important for hippocampal learning and memory. In this network controlling CaMKII autophosphorylation is a bistable work we show that CaMKII exhibits an intriguing switch-like type of switch that allows CaMKII to remain autophosphory- activation that likely is important for changes in synaptic strength. lated long after Ca2ϩ returns to a basal level (16). We found that autophosphorylation of CaMKII by itself showed a In this work we demonstrate experimentally that CaMKII 2؉ Ϸ ϩ steep dependence on Ca concentration [Hill coefficient (nH) 5]. responds in a switch-like fashion to Ca2 : CaMKII transitions 2؉ Ϸ However, an even steeper Ca dependence (nH 8) was observed rapidly from little to near-total autophosphorylation over a when autophosphorylation is balanced by the dephosphorylation narrow range of Ca2ϩ. Interestingly, this switch-like response was activity of protein phosphatase 1 (PP1). -
A Modular Approach for Modeling the Cell Cycle Based on Functional Response Curves
bioRxiv preprint doi: https://doi.org/10.1101/2021.04.28.441747; this version posted April 28, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. A modular approach for modeling the cell cycle based on functional response curves Jolan De Boeck1,2, Jan Rombouts1, Lendert Gelens1*, 1 Laboratory of Dynamics in Biological Systems, Department of Cellular and Molecular Medicine, University of Leuven, 3000 Leuven, Belgium 2 Stem Cell Institute Leuven, Department of Development and Regeneration, University of Leuven, 3000 Leuven, Belgium * [email protected] Abstract Modeling biochemical reactions by means of differential equations often results in systems with a large number of variables and parameters. As this might complicate the interpretation and generalization of the obtained results, it is often desirable to reduce the complexity of the model. One way to accomplish this is by replacing the detailed reaction mechanisms of certain modules in the model by a mathematical expression that qualitatively describes the dynamical behavior of these modules. Such an approach has been widely adopted for ultrasensitive responses, for which underlying reaction mechanisms are often replaced by a single Hill equation. Also time delays are usually accounted for by using an explicit delay in delay differential equations. In contrast, however, S-shaped response curves, which are often encountered in bistable systems, are not easily modeled in such an explicit way. Here, we extend the classical Hill function into a mathematical expression that can be used to describe both ultrasensitive and S-shaped responses. -
The Goldbeter-Koshland Switch in the First-Order Region and Its Response to Dynamic Disorder
The Goldbeter-Koshland switch in the first-order region and its response to dynamic disorder Jianhua Xing1, 2, 4, Jing Chen3 1. Chemistry, Materials, and Life Sciences Directorate, University of California & Lawrence Livermore National Laboratory, Livermore, CA 94550 2. Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061- 0406 3. Biophysics Graduate Program, University of California, Berkeley, Berkeley, CA 94720 4. Send correspondences to: [email protected] 1 Abstract In their classical work (Proc. Natl. Acad. Sci. USA, 1981, 78:6840-6844), Goldbeter and Koshland mathematically analyzed a reversible covalent modification system which is highly sensitive to the concentration of effectors. Its signal-response curve appears sigmoidal, constituting a biochemical switch. However, the switch behavior only emerges in the ‘zero-order region’, i.e. when the signal molecule concentration is much lower than that of the substrate it modifies. In this work we showed that the switching behavior can also occur under comparable concentrations of signals and substrates, provided that the signal molecules catalyze the modification reaction in cooperation. We also studied the effect of dynamic disorders on the proposed biochemical switch, in which the enzymatic reaction rates, instead of constant, appear as stochastic functions of time. We showed that the system is robust to dynamic disorder at bulk concentration. But if the dynamic disorder is quasi-static, large fluctuations of the switch response behavior may be observed at low concentrations. Such fluctuation is relevant to many biological functions. It can be reduced by either increasing the conformation interconversion rate of the protein, or correlating the enzymatic reaction rates in the network. -
A Phosphatase Threshold Sets the Level of Cdk1 Activity in Early Mitosis in Budding Yeast
A phosphatase threshold sets the level of Cdk1 activity in early mitosis in budding yeast a b,d c c Stacy L. Harvey , Germán Enciso , Noah E. Dephoure , Steven P. Gygi , Jeremy b a,* Gunawardena , and Douglas R. Kellogg a Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA 95064 b Department of Systems Biology, Harvard Medical School, Boston, MA 02115 c Department of Cell Biology, Harvard Medical School, Boston, MA 02115 d Present address: Department of Mathematics, University of California, Irvine, CA 92697 *Correspondence: [email protected] Running Head: PP2A-dependent modulation of Cdk1 activity ABSTRACT Entry into mitosis is initiated by synthesis of cyclins, which bind and activate cyclin- dependent kinase 1 (Cdk1). Cyclin synthesis is gradual, yet activation of Cdk1 occurs in a stepwise manner: a low level of Cdk1 activity is initially generated that triggers early mitotic events, which is followed by full activation of Cdk1. Little is known about how stepwise activation of Cdk1 is achieved. A key regulator of Cdk1 is the Wee1 kinase, which phosphorylates and inhibits Cdk1. Wee1 and Cdk1 show mutual regulation: Cdk1 phosphorylates Wee1, which activates Wee1 to inhibit Cdk1. Further phosphorylation events inactivate Wee1. We discovered that a specific form of protein phosphatase 2A (PP2ACdc55) opposes the initial phosphorylation of Wee1 by Cdk1. In vivo analysis, in vitro reconstitution and mathematical modeling suggest that PP2ACdc55 sets a threshold that limits activation of Wee1, thereby allowing a low constant level of Cdk1 activity to escape Wee1 inhibition in early mitosis. These results define a new role for PP2ACdc55 and reveal a systems-level mechanism by which dynamically opposed kinase and phosphatase activities can modulate signal strength. -
Temporal Pattern and Synergy Influence Activity of ERK Signaling Pathways During L-LTP Induction
RESEARCH ARTICLE Temporal pattern and synergy influence activity of ERK signaling pathways during L-LTP induction Nadiatou T Miningou Zobon1, Joanna Je˛drzejewska-Szmek2, Kim T Blackwell3,4* 1Department of Chemistry and Biochemistry, George Mason University, Fairfax, United States; 2Laboratory of Neuroinformatic, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland; 3Interdisciplinary Program in Neuroscience, Bioengineering Department, George Mason University, Fairfax, United States; 4Krasnow Institute for Advanced Study, George Mason University, Fairfax, United States Abstract Long-lasting long-term potentiation (L-LTP) is a cellular mechanism of learning and memory storage. Studies have demonstrated a requirement for extracellular signal-regulated kinase (ERK) activation in L-LTP produced by a diversity of temporal stimulation patterns. Multiple signaling pathways converge to activate ERK, with different pathways being required for different stimulation patterns. To answer whether and how different temporal patterns select different signaling pathways for ERK activation, we developed a computational model of five signaling pathways (including two novel pathways) leading to ERK activation during L-LTP induction. We show that calcium and cAMP work synergistically to activate ERK and that stimuli given with large intertrial intervals activate more ERK than shorter intervals. Furthermore, these pathways contribute to different dynamics of ERK activation. These results suggest that signaling pathways with different temporal sensitivities facilitate ERK activation to diversity of temporal patterns. *For correspondence: [email protected] Introduction Competing interests: The Temporal patterns are a key feature of the environment. The speed of traversing space is indicated authors declare that no by the time between spatial cues. In classical conditioning, adaptive changes in behavior require an competing interests exist. -
Phosphorylation Potential and Chemical Fluxes Govern The
Phosphorylation potential and chemical fluxes govern the biological performance of multiple PdP cycles Teng Wang1,3, Chenzi Jin2,3, Fangting Li2,3* 1School of Life Sciences, Peking University, Beijing 100871, China. 2 School of Physics, Peking University, Beijing 100871, China. 3 Center for Quantitative Biology, Peking University, Beijing 100871, China. * Correspondence: [email protected] Abstract Fission yeast G2/M transition is regulated by a biochemical reaction networks which contains four components: Cdc13, Cdc2, Wee1, and Cdc25. This circuit is characterized by the ultrasensitive responses of Wee1 or Cdc25 to Cdc13/Cdc2 activity, and the bistability of Cdc2 activation. Previous work has shown that this bistability is governed by phosphorylation energy. In this article, we developed the kinetic model of this circuit and conducted further thermodynamic analysis on the role of phosphorylation energy ( ∆G ). We showed that ∆G level shapes the response curves of Wee1 or Cdc25 to Cdc2 and governs the intrinsic noise level of Cdc2 activity. More importantly, the mutually antagonistic chemical fluxes around the PdP cycles in G2/M circuit were shown to act as a stabilizer of Cdc2 activity against ∆G fluctuations. These results suggest the fundamental role of free energy and chemical fluxes on the sensitivity, bistability and robustness of G2/M transition. Introduction The onset of mitosis is one of the major events during eukaryotic cell cycle (1). The irreversibility of this transition from G2 phase to M phase, which means that the cell persists in the M state after the driving factors is withdrawn, is crucial for cells because it ensures the unidirectional of cell cycle and provides the robustness against cellular noises (2, 3). -
Pharmacological Targeting of the Mitochondrial Phosphatase PTPMT1 by Dahlia Doughty Shenton Department of Biochemistry Duke
Pharmacological Targeting of the Mitochondrial Phosphatase PTPMT1 by Dahlia Doughty Shenton Department of Biochemistry Duke University Date: May 1 st 2009 Approved: ___________________________ Dr. Patrick J. Casey, Supervisor ___________________________ Dr. Perry J. Blackshear ___________________________ Dr. Anthony R. Means ___________________________ Dr. Christopher B. Newgard ___________________________ Dr. John D. York Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry in the Graduate School of Duke University 2009 ABSTRACT Pharmacological Targeting of the Mitochondrial Phosphatase PTPMT1 by Dahlia Doughty Shenton Department of Biochemistry Duke University Date: May 1 st 2009 Approved: ___________________________ Dr. Patrick J. Casey, Supervisor ___________________________ Dr. Perry J. Blackshear ___________________________ Dr. Anthony R. Means ___________________________ Dr. Christopher B. Newgard ___________________________ Dr. John D. York An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry in the Graduate School of Duke University 2009 Copyright by Dahlia Doughty Shenton 2009 Abstract The dual specificity protein tyrosine phosphatases comprise the largest and most diverse group of protein tyrosine phosphatases and play integral roles in the regulation of cell signaling events. The dual specificity protein tyrosine phosphatases impact multiple