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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2008.02.041 Byline: Yongna Xing (1), Zhu Li (1), Yu Chen (1), Jeffry B. Stock (1), Philip D. Jeffrey (1), Yigong Shi (1) Keywords: PROTEINS; SIGNALING Abstract: Protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that plays a role in many biological processes. Reversible carboxyl methylation of the PP2A catalytic subunit is an essential regulatory mechanism for its function. Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. However, the underlying mechanism of PME-1 function remains enigmatic. Here we report the crystal structures of PME-1 by itself and in complex with a PP2A heterodimeric core enzyme. The structures reveal that PME-1 directly binds to the active site of PP2A and that this interaction results in the activation of PME-1 by rearranging the catalytic triad into an active conformation. Strikingly, these interactions also lead to inactivation of PP2A by evicting the manganese ions that are required for the phosphatase activity of PP2A. These observations identify a dual role of PME-1 that regulates PP2A activation, methylation, and holoenzyme assembly in cells. Author Affiliation: (1) Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Princeton, NJ 08544, USA Article History: Received 29 November 2007; Revised 14 January 2008; Accepted 8 February 2008 Article Note: (miscellaneous) Published: April 3, 2008

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2006.01.010 Byline: Peter A. Thomason (a)(c), Satoshi Sawai (a), Jeffry B. Stock (a)(b), Edward C. Cox (a) Keywords: Morphogenesis; Dictyostelium; Histidine kinase; dhkK; Slugger; Culmination; Phosphorelay; Cyclic AMP Abstract: A key event in Dictyostelium development is the formation of the Mexican hat. This corresponds to a commitment step in morphogenesis that irreversibly signals progression from the slug stage to the fruiting body. We describe the characterization of the dhkK gene that controls this morphogenetic step. Null mutants of dhkK repeatedly attempt, and fail, to undergo morphogenesis from the slug to the Mexican hat, causing them to exhibit a 'slugger' phenotype, which cannot be corrected by co-development with wild-type cells. The dhkK gene encodes a putative receptor histidine kinase whose expression is enriched in prestalk cells in the slug. Uniquely for a histidine kinase, DhkK is located in the nuclear envelope. Entry into culmination requires the DhkK response regulator domain, which appears to directly regulate cyclic AMP signaling. Author Affiliation: (a) Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA (b) Department of Chemistry, Princeton University, Princeton, NJ 08544, USA (c) School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Article History: Received 15 June 2005; Revised 31 August 2005; Accepted 9 January 2006

Abstract: Phosphorylation is a key post-translational modification for cellular signaling, and abnormalities in this process are observed in several neurodegenerative disorders. Among these disorders, Parkinson’s disease (PD) is particularly intriguing as there are both genetic causes of disease that involve phosphorylation, and pathological hallmarks of disease composed of a hyperphosphorylated protein. Two of the major genes linked to PD are themselves kinases – leucine rich repeat kinase 2 (LRRK2) and phosphatase and tensin induced homolog kinase 1 (PINK1). Mutations in LRRK2 lead to its increased kinase activity and dominantly inherited PD, while mutations in PINK1 lead to loss of function and recessive PD. A third genetic linkage to disease is α-synuclein, a protein that is heavily phosphorylated in Lewy bodies and Lewy neurites, the pathological hallmarks of PD. The phosphorylation of α-synuclein at various residues influences its aggregation, either positively or negatively, thereby impacting its central role in disease pathogenesis. Given these associations of phosphorylation with PD, modulation of this modification is an attractive therapeutic strategy. The kinases that act in these disease relevant pathways have been the primary target for such approaches. But, the development of kinase inhibitors has been complicated by the necessary specificity to retain safety, the redundancy of kinases leading to lack of efficacy, and the difficulties in overcoming the blood–brain barrier. The field of modulating phosphatases has the potential to overcome some of these issues and provide the next generation of therapeutic targets for PD. In this review, we address the phosphorylation pathways involved in PD, the kinases and issues related to their inhibition, and the evolving field of the phosphatases relevant in PD and how they may be targeted pharmacologically. [Copyright &y& Elsevier]

Motile bacteria regulate chemotaxis through a highly conserved chemosensory signal-transduction system. System-wide analyses and mathematical modeling are facilitated by extensive experimental observations regarding bacterial chemotaxis proteins, including biochemical parameters, protein structures and protein–protein interaction maps. Thousands of signaling and regulatory chemotaxis proteins within a bacteria cell form a highly interconnected network through distinct protein–protein interactions. A bacterial cell is able to respond to multiple stimuli through a collection of chemoreceptors with different sensory modalities, which interact to affect the cooperativity and sensitivity of the chemotaxis response. The robustness or insensitivity of the chemotaxis system to perturbations in biochemical parameters is a product of the system''s hierarchical network architecture. [Copyright &y& Elsevier]

Bacteria can detect and respond to a remarkably diverse set of environmental conditions. This ability enables motile species to integrate stimuli, to compare current surroundings with those of the recent past, and to adjust swimming behavior to move up gradients of attractants and avoid repellents. Many of the molecular details involved in the bacterial chemotaxis system have been elucidated. Several models have been proposed recently to explain how cells process external information through a patch of highly interactive transmembrane receptors and transduce this information to other components in the cytoplasm that, in turn, function to regulate motility. [Copyright &y& Elsevier]

Long term consequence of non-fatal overdose in people who use opioids are not well understood. The intermittent exposure to non-fatal overdose leads to a tauopathy that is often accompanied by abrogated neuroprotective response, abnormal amyloid processing and other pathologies. The scope and limitations of available literature are discussed including neuropathologies associated with opioid and overdose exposures, contributing comorbidities and proteinopathies. Contrasting postmortem data of overdose victims with animal models of opioid neuropathologies and hypoxic injury paints a picture distinct from other proteinopathies as well as effects of moderate opioid exposure. Furthermore the reported biochemical changes and potential targets for therapeutic intervention were mapped pointing to underlying imbalance between tau kinases and phosphatases that is characteristic of Alzheimer Disease. • Opioid overdose leads to abnormal amyloid processing and hyperphosphorylated tau. • People who use opioids have misbalance in tau kinases and phosphatases. • The neuropathology of non-fatal overdose is consistent with early Alzheimer disease. • Neuropathological changes of a non-fatal overdose are summarized. [ABSTRACT FROM AUTHOR]

A minor component of coffee unrelated to caffeine, eicosanoyl-5-hydroxytryptamide (EHT), provides protection in a rat model for Alzheimer's disease (AD). In this model, viral expression of the phosphoprotein phosphatase 2A (PP2A) endogenous inhibitor, the I 2 PP 2 A , or SET protein in the brains of rats leads to several characteristic features of AD including cognitive impairment, tau hyperphosphorylation, and elevated levels of cytoplasmic amyloid-β protein. Dietary supplementation with EHT for 6–12 months resulted in substantial amelioration of all these defects. The beneficial effects of EHT could be associated with its ability to increase PP2A activity by inhibiting the demethylation of its catalytic subunit PP2Ac. These findings raise the possibility that EHT may make a substantial contribution to the apparent neuroprotective benefits associated with coffee consumption as evidenced by numerous epidemiologic studies indicating that coffee drinkers have substantially lowered risk of developing AD. [ABSTRACT FROM AUTHOR]

N-Acetyl-S-farnesyl-L-cysteine (AFC), a modulator of G protein and G-protein coupled receptor signaling, inhibits neutrophil chemotaxis and other inflammatory responses in cell-based assays. Here, we show topical AFC inhibits in vivo acute inflammation induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and arachidonic acid using the mouse ear model of inflammation. AFC inhibits edema, as measured by ear weight, and also inhibits neutrophil infiltration as assayed by direct counting in histological sections and by measuring myeloperoxidase (MPO) activity as a neutrophil marker. In addition, AFC inhibits in vivo allergic contact dermatitis in a mouse model utilizing sensitization followed by a subsequent challenge with 2,4-dinitrofluorobenzene. Unlike the established anti-inflammatories dexamethasone and indomethacin, AFC's action was restricted to the site of application. In this mouse model, both dexamethasone and indomethacin inhibited TPA-induced edema and MPO activity in the vehicle-treated, contralateral ear. AFC showed no contralateral ear inhibition for either of these end points. A marginally significant decrease due to AFC treatment was seen in TPA-induced epidermal hyperplasia at 24 hours. This was much less than the 90% inhibition of neutrophil infiltration, suggesting that AFC does not act by directly inhibiting protein kinase C.Journal of Investigative Dermatology (2008) 128, 643–654; doi:10.1038/sj.jid.5701061; published online 20 September 2007 [ABSTRACT FROM AUTHOR]