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The phosphocarrier protein HPr of the bacterial phosphotransferase system globally regulates energy metabolism by directly interacting with multiple enzymes in Escherichia coli.

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The phosphocarrier protein HPr of the bacterial phosphotransferase system globally regulates energy metabolism by directly interacting with multiple enzymes in Escherichia coli.

J Biol Chem. 2017 Aug 25;292(34):14250-14257

Authors: Rodionova IA, Zhang Z, Mehla J, Goodacre N, Babu M, Emili A, Uetz P, Saier MH

Abstract
The histidine-phosphorylatable phosphocarrier protein (HPr) is an essential component of the sugar-transporting phosphotransferase system (PTS) in many bacteria. Recent interactome findings suggested that HPr interacts with several carbohydrate-metabolizing enzymes, but whether HPr plays a regulatory role was unclear. Here, we provide evidence that HPr interacts with a large number of proteins in Escherichia coli We demonstrate HPr-dependent allosteric regulation of the activities of pyruvate kinase (PykF, but not PykA), phosphofructokinase (PfkB, but not PfkA), glucosamine-6-phosphate deaminase (NagB), and adenylate kinase (Adk). HPr is either phosphorylated on a histidyl residue (HPr-P) or non-phosphorylated (HPr). PykF is activated only by non-phosphorylated HPr, which decreases the PykF Khalf for phosphoenolpyruvate by 10-fold (from 3.5 to 0.36 mm), thus influencing glycolysis. PfkB activation by HPr, but not by HPr-P, resulted from a decrease in the Khalf for fructose-6-P, which likely influences both gluconeogenesis and glycolysis. Moreover, NagB activation by HPr was important for the utilization of amino sugars, and allosteric inhibition of Adk activity by HPr-P, but not by HPr, allows HPr to regulate the cellular energy charge coordinately with glycolysis. These observations suggest that HPr serves as a directly interacting global regulator of carbon and energy metabolism and probably of other physiological processes in enteric bacteria.

PMID: 28634232 [PubMed - indexed for MEDLINE]



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Multiple functions of protein phosphatases in receptor tyrosine kinase signaling revealed by interactome analysis.

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Multiple functions of protein phosphatases in receptor tyrosine kinase signaling revealed by interactome analysis.

Mol Cell Oncol. 2017;4(3):e1297101

Authors: Yao Z, Stagljar I

Abstract
To obtain a global picture of how protein phosphatases are involved in receptor tyrosine kinase (RTK) signaling, we mapped the RTK-phosphatase interactome. Analyses of selected interactions revealed detailed mechanisms of their actions. This study provides new knowledge to better understand cancer development and to identify novel therapeutic targets.

PMID: 28616575 [PubMed - in process]



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Intertumoral Heterogeneity within Medulloblastoma Subgroups.

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Intertumoral Heterogeneity within Medulloblastoma Subgroups.

Cancer Cell. 2017 Jun 12;31(6):737-754.e6

Authors: Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, Garzia L, Torchia J, Nor C, Morrissy AS, Agnihotri S, Thompson YY, Kuzan-Fischer CM, Farooq H, Isaev K, Daniels C, Cho BK, Kim SK, Wang KC, Lee JY, Grajkowska WA, Perek-Polnik M, Vasiljevic A, Faure-Conter C, Jouvet A, Giannini C, Nageswara Rao AA, Li KKW, Ng HK, Eberhart CG, Pollack IF, Hamilton RL, Gillespie GY, Olson JM, Leary S, Weiss WA, Lach B, Chambless LB, Thompson RC, Cooper MK, Vibhakar R, Hauser P, van Veelen MC, Kros JM, French PJ, Ra YS, Kumabe T, López-Aguilar E, Zitterbart K, Sterba J, Finocchiaro G, Massimino M, Van Meir EG, Osuka S, Shofuda T, Klekner A, Zollo M, Leonard JR, Rubin JB, Jabado N, Albrecht S, Mora J, Van Meter TE, Jung S, Moore AS, Hallahan AR, Chan JA, Tirapelli DPC, Carlotti CG, Fouladi M, Pimentel J, Faria CC, Saad AG, Massimi L, Liau LM, Wheeler H, Nakamura H, Elbabaa SK, Perezpeña-Diazconti M, Chico Ponce de León F, Robinson S, Zapotocky M, Lassaletta A, Huang A, Hawkins CE, Tabori U, Bouffet E, Bartels U, Dirks PB, Rutka JT, Bader GD, Reimand J, Goldenberg A, Ramaswamy V, Taylor MD

Abstract
While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

PMID: 28609654 [PubMed - indexed for MEDLINE]



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Pre-concentration by liquid intake by paper (P-CLIP): a new technique for large volumes and digital microfluidics.

Pre-concentration by liquid intake by paper (P-CLIP): a new technique for large volumes and digital microfluidics.

Lab Chip. 2017 Jun 12;:

Authors: Rackus DG, de Campos RPS, Chan C, Karcz MM, Seale B, Narahari T, Dixon C, Chamberlain MD, Wheeler AR

Abstract
Microfluidic platforms are an attractive option for incorporating complex fluid handling into low-cost and rapid diagnostic tests. A persistent challenge for microfluidics, however, is the mismatch in the "world-to-chip" interface - it is challenging to detect analytes present at low concentrations in systems that can only handle small volumes of sample. Here we describe a new technique termed pre-concentration by liquid intake by paper (P-CLIP) that addresses this mismatch, allowing digital microfluidics to interface with volumes on the order of hundreds of microliters. In P-CLIP, a virtual microchannel is generated to pass a large volume through the device; analytes captured on magnetic particles can be isolated and then resuspended into smaller volumes for further processing and analysis. We characterize this method and demonstrate its utility with an immunoassay for Plasmodium falciparum lactate dehydrogenase, a malaria biomarker, and propose that the P-CLIP strategy may be useful for a wide range of applications that are currently limited by low-abundance analytes.

PMID: 28604891 [PubMed - as supplied by publisher]



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Rab7 palmitoylation is required for efficient endosome-to-TGN trafficking.

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Rab7 palmitoylation is required for efficient endosome-to-TGN trafficking.

J Cell Sci. 2017 Jun 09;:

Authors: Modica G, Skorobogata O, Sauvageau E, Vissa A, Yip CM, Kim PK, Wurtele H, Lefrancois S

Abstract
Retromer is a multimeric protein complex that mediates endosome-to-TGN and endosome-to-plasma membrane trafficking of integral membrane proteins. Dysfunction of this complex has been linked to Alzheimer's and Parkinson's disease. The recruitment of retromer to endosomes is regulated by Rab7 to coordinate endosome-to- TGN trafficking of cargo-receptor complexes. Rab7 is also required for the degradation of internalized integral membrane proteins such as the epidermal growth factor receptor. We found that Rab7 is palmitoylated and that this modification is not required for membrane anchoring. Palmitoylated Rab7 co-localizes efficiently with and has a higher propensity to interact with retromer than non-palmitoylatable Rab7. Rescue of Rab7 knock out cells by expressing wild-type Rab7 restores efficient endosome-to-TGN trafficking, while rescue with non-palmitoylatable Rab7 does not. Interestingly, Rab7 palmitoylation does not appear to be required for the degradation of epidermal growth factor receptor receptor nor its interaction with its effector RILP. Overall, our results indicate that Rab7 palmitoylation is required for the spatiotemporal recruitment of retromer and efficient endosome-to-TGN Network trafficking of the lysosomal sorting receptors.

PMID: 28600323 [PubMed - as supplied by publisher]



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In vitro maturation of human iPS-derived neuroepithelial cells influences transplant survival in the stroke-injured rat brain.

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In vitro maturation of human iPS-derived neuroepithelial cells influences transplant survival in the stroke-injured rat brain.

Tissue Eng Part A. 2017 Jun 08;:

Authors: Payne SL, Anandakumaran PN, Varga BV, Morshead CM, Nagy A, Shoichet MS

Abstract
Stem cell transplantation is a promising strategy for brain tissue regeneration; yet, despite some success, cell survival following transplantation remains low. Here we demonstrate that cell viability is enhanced by control over maturation of neuronal precursor cells, which are delivered in an injectable blend of hyaluronan (HA) and methylcellulose (MC) (HAMC). We selected three subpopulations of human neuronal precursor cells derived from a cortically-specified neuroepithelial stem cell (cNESC) population based on differences in expression of multipotent and neuron-specific proteins: early, mid-, and late-differentiated neurons. These cells were transplanted into an endothelin-1 stroke-injured rat brain and their survival and fate were investigated one week later. Significantly more cells were found in the brain after transplanting early or mid- differentiated cNESCs compared to the late-differentiated population. The mid-differentiated population also had significantly more β-III tubulin-positive cells than either the early or late-differentiated populations. These results suggest that maturity has a significant impact on cell survival following transplantation, and that cells with an intermediate maturity differentiate to neurons.

PMID: 28594288 [PubMed - as supplied by publisher]



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Environmental Factors That Influence Stem Cell Migration: An "Electric Field".

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Environmental Factors That Influence Stem Cell Migration: An "Electric Field".

Stem Cells Int. 2017;2017:4276927

Authors: Iwasa SN, Babona-Pilipos R, Morshead CM

Abstract
Environmental Stimulus of Electric Fields on Stem Cell Migration. The movement of cells in response to electric potential gradients is called galvanotaxis. In vivo galvanotaxis, powered by endogenous electric fields (EFs), plays a critical role during development and wound healing. This review aims to provide a perspective on how stem cells transduce EFs into directed migration and an understanding of the current literature relating to the mechanisms by which cells sense and transduce EFs. We will comment on potential EF-based regenerative medicine therapeutics.

PMID: 28588621 [PubMed - in process]



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Generation and validation of intracellular ubiquitin variant inhibitors for USP7 and USP10.

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Generation and validation of intracellular ubiquitin variant inhibitors for USP7 and USP10.

J Mol Biol. 2017 Jun 03;:

Authors: Zhang W, Sartori MA, Makhnevych T, Federowicz KE, Dong X, Liu L, Nim S, Dong A, Yang J, Li Y, Haddad D, Ernst A, Heerding D, Tong Y, Moffat J, Sidhu SS

Abstract
Post-translational modification of the p53 signaling pathway plays an important role in cell cycle progression and stress-induced apoptosis. Indeed, a large body of work has shown that dysregulation of p53 and its E3 ligase MDM2 by the ubiquitin-proteasome system (UPS) promotes carcinogenesis and malignant transformation. Thus, drug discovery efforts have focused on restoration of wild-type p53 activity or inactivation of oncogenic mutant p53 by targeted inhibition of UPS components, particularly key deubiquitinases (DUBs) of the ubiquitin-specific protease (USP) class. However, development of selective small molecule USP inhibitors has been challenging, partly due to the highly conserved structural features of the catalytic sites across the class. To tackle this problem, we devised a protein engineering strategy for rational design of inhibitors for DUBs and other UPS proteins. We employed a phage-displayed ubiquitin variant (UbV) library to develop inhibitors targeting the DUBs USP7 and USP10, which are involved in regulating levels of p53 and MDM2. We were able to identify UbVs that bound USP7 or USP10 with high affinity and inhibited deubiquitination activity. We solved the crystal structure of UbV.7.2 and rationalized the molecular basis for enhanced affinity and specificity for USP7. Finally, cell death was increased significantly by UbV.7.2 expression in a colon cancer cell line that was treated with the chemotherapy drug cisplatin, demonstrating the therapeutic potential of inhibiting USP7 by this approach.

PMID: 28587923 [PubMed - as supplied by publisher]



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Mechanisms of suppression: The wiring of genetic resilience.

Mechanisms of suppression: The wiring of genetic resilience.

Bioessays. 2017 Jun 05;:

Authors: van Leeuwen J, Pons C, Boone C, Andrews BJ

Abstract
Recent analysis of genome sequences has identified individuals that are healthy despite carrying severe disease-associated mutations. A possible explanation is that these individuals carry a second genomic perturbation that can compensate for the detrimental effects of the disease allele, a phenomenon referred to as suppression. In model organisms, suppression interactions are generally divided into two classes: genomic suppressors which are secondary mutations in the genome that bypass a mutant phenotype, and dosage suppression interactions in which overexpression of a suppressor gene rescues a mutant phenotype. Here, we describe the general properties of genomic and dosage suppression, with an emphasis on the budding yeast. We propose that suppression interactions between genetic variants are likely relevant for determining the penetrance of human traits. Consequently, an understanding of suppression mechanisms may guide the discovery of protective variants in healthy individuals that carry disease alleles, which could direct the rational design of new therapeutics.

PMID: 28582599 [PubMed - as supplied by publisher]



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Engineering cell fitness: lessons for regenerative medicine.

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Engineering cell fitness: lessons for regenerative medicine.

Curr Opin Biotechnol. 2017 May 25;47:7-15

Authors: Shakiba N, Zandstra PW

Abstract
Cell competition results in the loss of weaker cells and the dominance of stronger cells. So-called 'loser' cells are either removed by active elimination or by limiting their access to survival factors. Recently, competition has been shown to serve as a surveillance mechanism against emerging aberrant cells in both the developing and adult organism, contributing to overall organism fitness and survival. Here, we explore the origins and implications of cell competition in development, tissue homeostasis, and in vitro culture. We also provide a forward look on the use of cell competition to interpret multicellular dynamics while offering a perspective on harnessing competition to engineer cells with optimized and controllable fitness characteristics for regenerative medicine applications.

PMID: 28551499 [PubMed - as supplied by publisher]



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