Interrogation of kinase genetic interactions provides a global view of PAK1-mediated signal transduction pathways [Gene Regulation]
Kinases are critical components of intracellular signaling pathways and have been extensively investigated with regard to their roles in cancer. p21-activated kinase-1 (PAK1) is a serine/threonine kinase that has been previously implicated in numerous biological processes, such as cell migration, cell cycle progression, cell motility, invasion, and angiogenesis, in glioma and other cancers. However, the signaling network linked to PAK1 is not fully defined. We previously reported a large-scale yeast genetic interaction screen using toxicity as a readout to identify candidate PAK1 genetic interactions. En masse transformati...
Source: Journal of Biological Chemistry - December 11, 2020 Category: Chemistry Authors: Jae-Hong Kim, Yeojin Seo, Myungjin Jo, Hyejin Jeon, Young-Seop Kim, Eun-Jung Kim, Donggun Seo, Won-Ha Lee, Sang Ryong Kim, Nozomu Yachie, Quan Zhong, Marc Vidal, Frederick P. Roth, Kyoungho Suk Tags: Editors ' Picks Source Type: research
Withdrawal: Selective cleavage of BLM, the Bloom syndrome protein, during apoptotic cell death. [Withdrawals/Retractions]
This article has been withdrawn by the authors except Dr. Kohwi-Shigematsu, who could not be reached. Fig. 3B has a duplication of the top band in lanes 1 and 3. Fig. 5D has a duplication between the top bands and a horizontal flip of the bottom bands. Fig. 5E likewise has a duplication of the top bands excluding the probe lanes and a horizontal flip of the bottom bands. Fig. 6A has smaller microscopy images pasted on the background of larger microscopy images. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Oliver Bischof, Sanjeev Galande, Farzin Farzaneh, Terumi Kohwi-Shigematsu, Judith Campisi Tags: Withdrawals/Retractions Source Type: research
Naturally occurring hotspot cancer mutations in G{alpha}13 promote oncogenic signaling [Molecular Bases of Disease]
Heterotrimeric G-proteins are signaling switches broadly divided into four families based on the sequence and functional similarity of their Gα subunits: Gs, Gi/o, Gq/11, and G12/13. Artificial mutations that activate Gα subunits of each of these families have long been known to induce oncogenic transformation in experimental systems. With the advent of next-generation sequencing, activating hotspot mutations in Gs, Gi/o, or Gq/11 proteins have also been identified in patient tumor samples. In contrast, patient tumor-associated G12/13 mutations characterized to date lead to inactivation rather than activation. By using b...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Marcin Maziarz, Anthony Federico, Jingyi Zhao, Lorena Dujmusic, Zhiming Zhao, Stefano Monti, Xaralabos Varelas, Mikel Garcia-Marcos Tags: Accelerated Communications Source Type: research
Pluripotency of embryonic stem cells lacking clathrin-mediated endocytosis cannot be rescued by restoring cellular stiffness [Molecular Biophysics]
Mouse embryonic stem cells (mESCs) display unique mechanical properties, including low cellular stiffness in contrast to differentiated cells, which are stiffer. We have previously shown that mESCs lacking the clathrin heavy chain (Cltc), an essential component for clathrin-mediated endocytosis (CME), display a loss of pluripotency and an enhanced expression of differentiation markers. However, it is not known whether physical properties such as cellular stiffness also change upon loss of Cltc, similar to what is seen in differentiated cells, and if so, how these altered properties specifically impact pluripotency. Using a...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Ridim D. Mote, Jyoti Yadav, Surya Bansi Singh, Mahak Tiwari, Shinde Laxmikant V, Shivprasad Patil, Deepa Subramanyam Tags: Accelerated Communications Source Type: research
Molecular basis for histone H3 “K4me3-K9me3/2” methylation pattern readout by Spindlin1 [Gene Regulation]
Histone recognition by “reader” modules serves as a fundamental mechanism in epigenetic regulation. Previous studies have shown that Spindlin1 is a reader of histone H3K4me3 as well as “K4me3-R8me2a” and promotes transcription of rDNA or Wnt/TCF4 target genes. Here we show that Spindlin1 also acts as a potent reader of histone H3 “K4me3-K9me3/2” bivalent methylation pattern. Calorimetric titration revealed a binding affinity of 16 nm between Spindlin1 and H3 “K4me3-K9me3” peptide, which is one to three orders of magnitude stronger than most other histone readout events at peptide level. Structural studies r...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Fan Zhao, Yunan Liu, Xiaonan Su, Ji-Eun Lee, Yutong Song, Daliang Wang, Kai Ge, Juntao Gao, Michael Q. Zhang, Haitao Li Tags: Molecular Biophysics Source Type: research
Structural and biochemical characteristics of two Staphylococcus epidermidis RNase J paralogs RNase J1 and RNase J2 [Protein Structure and Folding]
RNase J enzymes are metallohydrolases that are involved in RNA maturation and RNA recycling, govern gene expression in bacteria, and catalyze both exonuclease and endonuclease activity. The catalytic activity of RNase J is regulated by multiple mechanisms which include oligomerization, conformational changes to aid substrate recognition, and the metal cofactor at the active site. However, little is known of how RNase J paralogs differ in expression and activity. Here we describe structural and biochemical features of two Staphylococcus epidermidis RNase J paralogs, RNase J1 and RNase J2. RNase J1 is a homodimer with exonuc...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Rishi Raj, Savitha Nadig, Twinkal Patel, Balasubramanian Gopal Tags: Protein Structure and Folding Source Type: research
Secretory galectin-3 induced by glucocorticoid stress triggers stemness exhaustion of hepatic progenitor cells [Signal Transduction]
Adult progenitor cell populations typically exist in a quiescent state within a controlled niche environment. However, various stresses or forms of damage can disrupt this state, which often leads to dysfunction and aging. We built a glucocorticoid (GC)-induced liver damage model of mice, found that GC stress induced liver damage, leading to consequences for progenitor cells expansion. However, the mechanisms by which niche factors cause progenitor cells proliferation are largely unknown. We demonstrate that, within the liver progenitor cells niche, Galectin-3 (Gal-3) is responsible for driving a subset of progenitor cells...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Fan Yang, Fan Zhang, Xueying Ji, Xin Jiang, Mengjuan Xue, Huiyuan Yu, Xiaona Hu, Zhijun Bao Tags: Cell Biology Source Type: research
Calpain activation mediates microgravity-induced myocardial abnormalities in mice via p38 and ERK1/2 MAPK pathways [Molecular Bases of Disease]
This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities. (Source: Journal of Biological Chemistry)
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Liwen Liang, Huili Li, Ting Cao, Lina Qu, Lulu Zhang, Guo-Chang Fan, Peter A. Greer, Jianmin Li, Douglas L. Jones, Tianqing Peng Tags: Molecular Bases of Disease Source Type: research
VBP1 modulates Wnt/{beta}-catenin signaling by mediating the stability of the transcription factors TCF/LEFs [Signal Transduction]
The Wnt/β-catenin pathway is one of the major pathways that regulates embryonic development, adult homeostasis, and stem cell self-renewal. In this pathway, transcription factors T-cell factor and lymphoid enhancer factor (TCF/LEF) serve as a key switch to repress or activate Wnt target gene transcription by recruiting repressor molecules or interacting with the β-catenin effector, respectively. It has become evident that the protein stability of the TCF/LEF family members may play a critical role in controlling the activity of the Wnt/β-catenin signaling pathway. However, factors that regulate the stability of TCF/LEFs...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Haifeng Zhang, Xiaozhi Rong, Caixia Wang, Yunzhang Liu, Ling Lu, Yun Li, Chengtian Zhao, Jianfeng Zhou Tags: Cell Biology Source Type: research
Functions of Gle1 are governed by two distinct modes of self-association [Gene Regulation]
Gle1 is a conserved, essential regulator of DEAD-box RNA helicases, with critical roles defined in mRNA export, translation initiation, translation termination, and stress granule formation. Mechanisms that specify which, where, and when DDXs are targeted by Gle1 are critical to understand. In addition to roles for stress-induced phosphorylation and inositol hexakisphosphate binding in specifying Gle1 function, Gle1 oligomerizes via its N-terminal domain in a phosphorylation-dependent manner. However, a thorough analysis of the role for Gle1 self-association is lacking. Here, we find that Gle1 self-association is driven by...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Aaron C. Mason, Susan R. Wente Tags: Cell Biology Source Type: research
Angiostatic cues from the matrix: Endothelial cell autophagy meets hyaluronan biology [Glycobiology and Extracellular Matrices]
The extracellular matrix encompasses a reservoir of bioactive macromolecules that modulates a cornucopia of biological functions. A prominent body of work posits matrix constituents as master regulators of autophagy and angiogenesis and provides molecular insight into how these two processes are coordinated. Here, we review current understanding of the molecular mechanisms underlying hyaluronan and HAS2 regulation and the role of soluble proteoglycan in affecting autophagy and angiogenesis. Specifically, we assess the role of proteoglycan-evoked autophagy in regulating angiogenesis via the HAS2-hyaluronan axis and ATG9A, a...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Carolyn G. Chen, Renato V. Iozzo Tags: JBC Reviews Source Type: research
Peptidoglycan analysis reveals that synergistic deacetylase activity in vegetative Clostridium difficile impacts the host response [Glycobiology and Extracellular Matrices]
Clostridium difficile is an anaerobic and spore-forming bacterium responsible for 15–25% of postantibiotic diarrhea and 95% of pseudomembranous colitis. Peptidoglycan is a crucial element of the bacterial cell wall that is exposed to the host, making it an important target for the innate immune system. The C. difficile peptidoglycan is largely N-deacetylated on its glucosamine (93% of muropeptides) through the activity of enzymes known as N-deacetylases, and this N-deacetylation modulates host–pathogen interactions, such as resistance to the bacteriolytic activity of lysozyme, virulence, and host innate immune response...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Heloise Coullon, Aline Rifflet, Richard Wheeler, Claire Janoir, Ivo G. Boneca, Thomas Candela Tags: Microbiology Source Type: research
Allosteric activation of proto-oncogene kinase Src by GPCR-beta-arrestin complexes [Enzymology]
G protein–coupled receptors (GPCRs) initiate signaling cascades via G-proteins and beta-arrestins (βarr). βarr-dependent actions begin with recruitment of βarr to the phosphorylated receptor tail and are followed by engagement with the receptor core. βarrs are known to act as adaptor proteins binding receptors and various effectors, but it is unclear whether in addition to the scaffolding role βarrs can allosterically activate their downstream targets. Here we demonstrate the direct allosteric activation of proto-oncogene kinase Src by GPCR–βarr complexes in vitro and establish the conformational basis of the act...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Natalia Pakharukova, Ali Masoudi, Biswaranjan Pani, Dean P. Staus, Robert J. Lefkowitz Tags: Signal Transduction Source Type: research
Calreticulin enhances the secretory trafficking of a misfolded {alpha}-1-antitrypsin [Protein Structure and Folding]
α1-antitrypsin (AAT) regulates the activity of multiple proteases in the lungs and liver. A mutant of AAT (E342K) called ATZ forms polymers that are present at only low levels in the serum and induce intracellular protein inclusions, causing lung emphysema and liver cirrhosis. An understanding of factors that can reduce the intracellular accumulation of ATZ is of great interest. We now show that calreticulin (CRT), an endoplasmic reticulum (ER) glycoprotein chaperone, promotes the secretory trafficking of ATZ, enhancing the media:cell ratio. This effect is more pronounced for ATZ than with AAT and is only partially depend...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Harihar Milaganur Mohan, Boning Yang, Nicole A. Dean, Malini Raghavan Tags: Protein Structure and Folding Source Type: research
ERAD deficiency promotes mitochondrial dysfunction and transcriptional rewiring in human hepatic cells [Cell Biology]
Mitochondrial dysfunction is associated with a variety of human diseases including neurodegeneration, diabetes, nonalcohol fatty liver disease (NAFLD), and cancer, but its underlying causes are incompletely understood. Using the human hepatic cell line HepG2 as a model, we show here that endoplasmic reticulum-associated degradation (ERAD), an ER protein quality control process, is critically required for mitochondrial function in mammalian cells. Pharmacological inhibition or genetic ablation of key proteins involved in ERAD increased cell death under both basal conditions and in response to proinflammatory cytokines, a si...
Source: Journal of Biological Chemistry - December 4, 2020 Category: Chemistry Authors: Qingqing Liu, Xiaoqin Yang, Guangyu Long, Yabing Hu, Zhenglong Gu, Yves R. Boisclair, Qiaoming Long Tags: Molecular Bases of Disease Source Type: research
