Oxygen-dependent changes in binding partners and post-translational modifications regulate the abundance and activity of HIF-1{alpha}/2{alpha}
Cellular adaptation to low-oxygen environments is mediated in part by the hypoxia-inducible factors (HIFs). Like other transcription factors, the stability and transcriptional activity of HIFs—and consequently, the hypoxic response—are regulated by post-translational modifications (PTMs) and changes in protein-protein interactions. Our current understanding of PTM-mediated regulation of HIFs is primarily based on in vitro protein fragment–based studies typically validated in fragment-expressing cells treated with hypoxia-mimicking compounds. Here, we used immunoprecipitation-based mass spectrometry to cha...
Source: Signal Transduction Knowledge Environment - July 20, 2021 Category: Science Authors: Daly, L. A., Brownridge, P. J., Batie, M., Rocha, S., See, V., Eyers, C. E. Tags: STKE Research Resource Source Type: news

Constrained TCR{gamma}{delta}-associated Syk activity engages PI3K to facilitate thymic development of IL-17A-secreting {gamma}{delta} T cells
Murine 17 cells, which are T cells that bear the T cell receptor (TCR) and secrete interleukin-17A (IL-17A), are generated in the thymus and are critical for various immune responses. Although strong TCR signals are required for the development of interferon- (IFN-)–secreting cells (IFN cells), the generation of 17 cells requires weaker TCR signaling. Here, we demonstrated that constrained activation of the kinase Syk downstream of TCR was required for the thymic development of 17 cells. Increasing or decreasing Syk activity by stimulating TCR or inhibiting Syk, respectively, substantially reduced 17 cell numbers. Th...
Source: Signal Transduction Knowledge Environment - July 20, 2021 Category: Science Authors: Sumaria, N., Martin, S., Pennington, D. J. Tags: STKE Research Articles Source Type: news

Throttling thermogenesis with neurotensin
Lymphatic endothelial cells release neurotensin to block thermogenesis in brown adipose tissue. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 20, 2021 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

The elongation factor eEF1A2 controls translation and actin dynamics in dendritic spines
Synaptic plasticity involves structural modifications in dendritic spines that are modulated by local protein synthesis and actin remodeling. Here, we investigated the molecular mechanisms that connect synaptic stimulation to these processes. We found that the phosphorylation of isoform-specific sites in eEF1A2—an essential translation elongation factor in neurons—is a key modulator of structural plasticity in dendritic spines. Expression of a nonphosphorylatable eEF1A2 mutant stimulated mRNA translation but reduced actin dynamics and spine density. By contrast, a phosphomimetic eEF1A2 mutant exhibited decrease...
Source: Signal Transduction Knowledge Environment - July 13, 2021 Category: Science Authors: Mendoza, M. B., Gutierrez, S., Ortiz, R., Moreno, D. F., Dermit, M., Dodel, M., Rebollo, E., Bosch, M., Mardakheh, F. K., Gallego, C. Tags: STKE Research Articles Source Type: news

Enhancing tumor infiltration
Targeting a chemokine receptor inhibitor enhances the trafficking of antitumor T cells into tumors. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 13, 2021 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

ETV7 limits antiviral gene expression and control of influenza viruses
In this study, we performed a CRISPR activation screen to identify previously unknown regulators of the type I IFN response. We identified the strongly induced ISG encoding ETS variant transcription factor 7 (ETV7) as a negative regulator of the type I IFN response. However, ETV7 did not uniformly suppress ISG transcription. Instead, ETV7 preferentially targeted a subset of antiviral ISGs that were particularly important for IFN-mediated control of influenza viruses. Together, our data assign a function for ETV7 as an IFN response regulator and also identify ETV7 as a potential therapeutic target to increase innate antivir...
Source: Signal Transduction Knowledge Environment - July 13, 2021 Category: Science Authors: Froggatt, H. M., Harding, A. T., Chaparian, R. R., Heaton, N. S. Tags: STKE Research Articles Source Type: news

Kynurenic acid may underlie sex-specific immune responses to COVID-19
This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 6, 2021 Category: Science Authors: Cai, Y., Kim, D. J., Takahashi, T., Broadhurst, D. I., Yan, H., Ma, S., Rattray, N. J. W., Casanovas-Massana, A., Israelow, B., Klein, J., Lucas, C., Mao, T., Moore, A. J., Muenker, M. C., Oh, J. E., Silva, J., Wong, P., Yale IMPACT Research team, Ko, A. Tags: STKE Research Resource Source Type: news

Long-chain polyphosphates impair SARS-CoV-2 infection and replication
Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO43–) units linked together by multiple high-energy phosphoanhydride bonds. In addition to being a source of energy, polyPs have cytoprotective and antiviral activities. Here, we investigated the antiviral activities of long-chain polyPs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In molecular docking analyses, polyPs interacted with several conserved amino acid residues in angiotensin-converting enzyme 2 (ACE2), the host receptor that facilitates virus entry, and in viral RNA-dependent RNA polym...
Source: Signal Transduction Knowledge Environment - July 6, 2021 Category: Science Authors: Ferrucci, V., Kong, D.-Y., Asadzadeh, F., Marrone, L., Boccia, A., Siciliano, R., Criscuolo, G., Anastasio, C., Quarantelli, F., Comegna, M., Pisano, I., Passariello, M., Iacobucci, I., Monica, R. D., Izzo, B., Cerino, P., Fusco, G., Viscardi, M., Brandi, Tags: STKE Research Articles Source Type: news

Complex CAFs
Diversity among cancer-associated fibroblasts from cholangiocarcinomas reveals distinct roles in tumor progression. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 6, 2021 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-{kappa}B and Notch signaling
The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling. In the cytosol, RAP1 bound t...
Source: Signal Transduction Knowledge Environment - June 29, 2021 Category: Science Authors: Robinson, N. J., Miyagi, M., Scarborough, J. A., Scott, J. G., Taylor, D. J., Schiemann, W. P. Tags: STKE Research Articles Source Type: news

Mn2+ coordinates Cap-0-RNA to align substrates for efficient 2'-O-methyl transfer by SARS-CoV-2 nsp16
Capping of viral messenger RNAs is essential for efficient translation, for virus replication, and for preventing detection by the host cell innate response system. The SARS-CoV-2 genome encodes the 2'-O-methyltransferase nsp16, which, when bound to the coactivator nsp10, uses S-adenosylmethionine (SAM) as a donor to transfer a methyl group to the first ribonucleotide of the mRNA in the final step of viral mRNA capping. Here, we provide biochemical and structural evidence that this reaction requires divalent cations, preferably Mn2+, and a coronavirus-specific four-residue insert. We determined the x-ray structures of the ...
Source: Signal Transduction Knowledge Environment - June 29, 2021 Category: Science Authors: Minasov, G., Rosas-Lemus, M., Shuvalova, L., Inniss, N. L., Brunzelle, J. S., Daczkowski, C. M., Hoover, P., Mesecar, A. D., Satchell, K. J. F. Tags: STKE Research Articles Source Type: news

Distributing apoptosis protects epithelia
EGFR signaling protects the integrity of epithelia by ensuring that apoptosis events are limited in both space and time. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - June 29, 2021 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

RAP1 moonlights to activate NF-{kappa}B and Notch in ALT
Cancer cells activate either telomerase or telomere recombination (ALT) to maintain telomere length and achieve immortalization. In this issue of Science Signaling, Robinson et al. reveal an unanticipated role of the protein SLX4IP in the SUMOylation of RAP1, which enhances its extratelomeric function in activating an NF-B–Notch signaling axis that favors ALT. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - June 29, 2021 Category: Science Authors: Churikov, D., Geli, V. Tags: STKE Focus Source Type: news

Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion and inhibits hepatocyte differentiation
In the adult liver, a population of facultative progenitor cells called biliary epithelial cells (BECs) proliferate and differentiate into cholangiocytes and hepatocytes after injury, thereby restoring liver function. In mammalian models of chronic liver injury, Notch signaling is essential for bile duct formation from these cells. However, the continual proliferation of BECs and differentiation of hepatocytes in these models have limited their use for determining whether Notch signaling is required for BECs to replenish hepatocytes after injury in the mammalian liver. Here, we used a temporally restricted model of hepatic...
Source: Signal Transduction Knowledge Environment - June 22, 2021 Category: Science Authors: Minnis-Lyons, S. E., Ferreira-Gonzalez, S., Aleksieva, N., Man, T. Y., Gadd, V. L., Williams, M. J., Guest, R. V., Lu, W.-Y., Dwyer, B. J., Jamieson, T., Nixon, C., Van Hul, N., Lemaigre, F. P., McCafferty, J., Leclercq, I. A., Sansom, O. J., Boulter, L., Tags: STKE Research Articles Source Type: news

Leaving the damage behind
A mechanism by which migrating cells shed defective mitochondria is identified. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - June 22, 2021 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

TSHZ2 is an EGF-regulated tumor suppressor that binds to the cytokinesis regulator PRC1 and inhibits metastasis
Unlike early transcriptional responses to mitogens, later events are less well-characterized. Here, we identified delayed down-regulated genes (DDGs) in mammary cells after prolonged treatment with epidermal growth factor (EGF). The expression of these DDGs was low in mammary tumors and correlated with prognosis. The proteins encoded by several DDGs directly bind to and inactivate oncoproteins and might therefore act as tumor suppressors. The transcription factor teashirt zinc finger homeobox 2 (TSHZ2) is encoded by a DDG, and we found that overexpression of TSHZ2 inhibited tumor growth and metastasis and accelerated mamma...
Source: Signal Transduction Knowledge Environment - June 22, 2021 Category: Science Authors: Uribe, M. L., Dahlhoff, M., Batra, R. N., Nataraj, N. B., Haga, Y., Drago-Garcia, D., Marrocco, I., Sekar, A., Ghosh, S., Vaknin, I., Lebon, S., Kramarski, L., Tsutsumi, Y., Choi, I., Rueda, O. M., Caldas, C., Yarden, Y. Tags: STKE Research Articles Source Type: news

Combinatorial phosphorylation modulates the structure and function of the G protein {gamma} subunit in yeast
Intrinsically disordered regions (IDRs) in proteins are often targets of combinatorial posttranslational modifications, which serve to regulate protein structure and function. Emerging evidence suggests that the N-terminal tails of G protein subunits, which are essential components of heterotrimeric G proteins, are intrinsically disordered, phosphorylation-dependent determinants of G protein signaling. Here, we found that the yeast G subunit Ste18 underwent combinatorial, multisite phosphorylation events within its N-terminal IDR. G protein–coupled receptor (GPCR) activation and osmotic stress induced phosphorylation...
Source: Signal Transduction Knowledge Environment - June 22, 2021 Category: Science Authors: Nassiri Toosi, Z., Su, X., Austin, R., Choudhury, S., Li, W., Pang, Y. T., Gumbart, J. C., Torres, M. P. Tags: STKE Research Articles Source Type: news

Lymph nodes lose their nerve
Loss of sciatic innervation of the popliteal lymph node causes IFN-–dependent lymph node expansion. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - June 15, 2021 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

The transmembrane serine protease hepsin suppresses type I interferon induction by cleaving STING
Many viral proteases mediate the evasion of antiviral innate immunity by cleaving adapter proteins in the interferon (IFN) induction pathway. Host proteases are also involved in innate immunity and inflammation. Here, we report that the transmembrane protease hepsin (also known as TMPRSS1), which is predominantly present in hepatocytes, inhibited the induction of type I IFN during viral infections. Knocking out hepsin in mouse embryonic fibroblasts (MEFs) increased the viral infection–induced expression of Ifnb1, an Ifnb1 promoter reporter, and an IFN-sensitive response element promoter reporter. Ectopic expression o...
Source: Signal Transduction Knowledge Environment - June 15, 2021 Category: Science Authors: Hsin, F., Hsu, Y.-C., Tsai, Y.-F., Lin, S.-W., Liu, H. M. Tags: STKE Research Articles Source Type: news

The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse
Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic activation, including during chronic infection and in solid tumors. Thus, Tim-3 is generally thought of as an inhibitory protein. We and others previously reported that under some circumstances, Tim-3 exerts paradoxical costimulatory activity in T cells (and other cells), including enhancement of the phosphorylation of ribosomal S6 protein. Here, we examined the upstream signaling pathways that control Tim-3–mediated increases in phosphorylated S6 in T cells. We also defined the localization of Tim-3 relative to the ...
Source: Signal Transduction Knowledge Environment - June 15, 2021 Category: Science Authors: Kataoka, S., Manandhar, P., Lee, J., Workman, C. J., Banerjee, H., Szymczak-Workman, A. L., Kvorjak, M., Lohmueller, J., Kane, L. P. Tags: STKE Research Articles Source Type: news

From lactate to antidepressant
The metabolism of lactic acid has antidepressant effects in mice. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - June 8, 2021 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Metabolic perturbations sensitize triple-negative breast cancers to apoptosis induced by BH3 mimetics
Cancer cells have differential metabolic dependencies compared to their nonmalignant counterparts. However, few metabolism-targeting compounds have been successful in clinical trials. Here, we investigated the metabolic vulnerabilities of triple-negative breast cancer (TNBC), particularly those metabolic perturbations that increased mitochondrial apoptotic priming and sensitivity to BH3 mimetics (drugs that antagonize antiapoptotic proteins). We used high-throughput dynamic BH3 profiling (HT-DBP) to screen a library of metabolism-perturbing small molecules, which revealed inhibitors of the enzyme nicotinamide phosphoribosy...
Source: Signal Transduction Knowledge Environment - June 8, 2021 Category: Science Authors: Daniels, V. W., Zoeller, J. J., van Gastel, N., McQueeney, K. E., Parvin, S., Potter, D. S., Fell, G. G., Ferreira, V. G., Yilma, B., Gupta, R., Spetz, J., Bhola, P. D., Endress, J. E., Harris, I. S., Carrilho, E., Sarosiek, K. A., Scadden, D. T., Brugge, Tags: STKE Research Articles Source Type: news

Kindlin-3 disrupts an intersubunit association in the integrin LFA1 to trigger positive feedback activation by Rap1 and talin1
Integrin activation by the intracellular adaptor proteins talin1 and kindlin-3 is essential for lymphocyte adhesion. These adaptors cooperatively control integrin activation through bidirectional (inside-out and outside-in) activation signals. Using single-molecule measurements, we revealed the distinct dynamics of talin1 and kindlin-3 interactions with the integrin LFA1 (αLβ2) and their functions in LFA1 activation and LFA1-mediated adhesion. The kinetics of talin1 binding to the tail of the β2 subunit corresponded to those of LFA1 binding to its ligand ICAM1. ICAM1 binding induced transient interactions b...
Source: Signal Transduction Knowledge Environment - June 8, 2021 Category: Science Authors: Kondo, N., Ueda, Y., Kinashi, T. Tags: STKE Research Articles Source Type: news

Time to ditch topical antibiotics?
Commensals promote skin regeneration and wound healing by stimulating IL-1β signaling in keratinocytes. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - June 1, 2021 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Yorkie drives Ras-induced tumor progression by microRNA-mediated inhibition of cellular senescence
The activation of Ras signaling is a major early event of oncogenesis in many contexts, yet paradoxically, Ras signaling induces cellular senescence, which prevents tumorigenesis. Thus, Ras-activated cells must overcome senescence to develop into cancer. Through a genetic screen in Drosophila melanogaster, we found that the ETS family transcriptional activator Pointed (Pnt) was necessary and sufficient to trigger cellular senescence upon Ras activation and blocked Ras-induced tumor growth in eye-antennal discs. Through analyses of mosaic discs using various genetic tools, we identified a mechanism of tumor progression in w...
Source: Signal Transduction Knowledge Environment - June 1, 2021 Category: Science Authors: Ito, T., Igaki, T. Tags: STKE Research Articles Source Type: news

Respiratory syncytial virus induces {beta}2-adrenergic receptor dysfunction in human airway smooth muscle cells
Pharmacologic agonism of the β2-adrenergic receptor (β2AR) induces bronchodilation by activating the enzyme adenylyl cyclase to generate cyclic adenosine monophosphate (cAMP). β2AR agonists are generally the most effective strategy to relieve acute airway obstruction in asthmatic patients, but they are much less effective when airway obstruction in young patients is triggered by infection with respiratory syncytial virus (RSV). Here, we investigated the effects of RSV infection on the abundance and function of β2AR in primary human airway smooth muscle cells (HASMCs) derived from pediatric lung tissue. ...
Source: Signal Transduction Knowledge Environment - June 1, 2021 Category: Science Authors: Harford, T. J., Rezaee, F., Gupta, M. K., Bokun, V., Naga Prasad, S. V., Piedimonte, G. Tags: STKE Research Articles Source Type: news

The bedside-bench-bedside cycle: Robert Lefkowitz and GPCRs
Biographies and autobiographies are important because they provide an account of history, social, cultural, and political developments, or discoveries and inventions, from a personal perspective. This is a review of the memoirs of Robert Lefkowitz (A Funny Thing Happened on the Way to Stockholm, with Randy Hall), who, together with Brian Kobilka, won the 2012 Nobel Prize in Chemistry for studies on G protein–coupled receptors. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - June 1, 2021 Category: Science Authors: Ciechanover, A. Tags: STKE Focus Source Type: news

The spatial distribution of target cell ligands determines NK cell degranulation
Cell-bound ligands are often viewed as moving passively in response to displacement of their cognate receptors. Verron et al. provide an example of the distribution of ligands influencing the functional outcome of receptor stimulation. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 25, 2021 Category: Science Authors: Veillette, A. Tags: STKE Focus Source Type: news

Forced into glucose metabolism
Glucose uptake through GLUT1 enables actin cytoskeletal reinforcement in response to mechanical strain. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 25, 2021 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

Phosphorylation of Pal2 by the protein kinases Kin1 and Kin2 modulates HAC1 mRNA splicing in the unfolded protein response in yeast
During cellular stress in the budding yeast Saccharomyces cerevisiae, an endoplasmic reticulum (ER)–resident dual kinase and RNase Ire1 splices an intron from HAC1 mRNA in the cytosol, thereby releasing its translational block. Hac1 protein then activates an adaptive cellular stress response called the unfolded protein response (UPR) that maintains ER homeostasis. The polarity-inducing protein kinases Kin1 and Kin2 contribute to HAC1 mRNA processing. Here, we showed that an RNA-protein complex that included the endocytic proteins Pal1 and Pal2 mediated HAC1 mRNA splicing downstream of Kin1 and Kin2. We found that Pal...
Source: Signal Transduction Knowledge Environment - May 25, 2021 Category: Science Authors: Ghosh, C., Uppala, J. K., Sathe, L., Hammond, C. I., Anshu, A., Pokkuluri, P. R., Turk, B. E., Dey, M. Tags: STKE Research Articles Source Type: news

NK cells integrate signals over large areas when building immune synapses but require local stimuli for degranulation
Immune synapses are large-scale, transient molecular assemblies that serve as platforms for antigen presentation to B and T cells and for target recognition by cytotoxic T cells and natural killer (NK) cells. The formation of an immune synapse is a tightly regulated, stepwise process in which the cytoskeleton, cell surface receptors, and intracellular signaling proteins rearrange into supramolecular activation clusters (SMACs). We generated artificial immune synapses (AIS) consisting of synthetic and natural ligands for the NK cell–activating receptors LFA-1 and CD16 by microcontact printing the ligands into circular...
Source: Signal Transduction Knowledge Environment - May 25, 2021 Category: Science Authors: Verron, Q., Forslund, E., Brandt, L., Leino, M., Frisk, T. W., Olofsson, P. E., Önfelt, B. Tags: STKE Research Articles Source Type: news

Growth factor-dependent ErbB vesicular dynamics couple receptor signaling to spatially and functionally distinct Erk pools
Growth factor–dependent vesicular dynamics allow cells to regulate the spatial distribution of growth factor receptors and thereby their coupling to downstream signaling effectors that guide cellular responses. We found that the ErbB ligands epidermal growth factor (EGF) and heregulin (HRG) generated distinct spatiotemporal patterns of cognate receptor activities to activate distinct subcellular pools of the extracellular signal–regulated kinase (Erk). Sustained plasma membrane activity of the receptor tyrosine kinases ErbB2/ErbB3 signaled to Erk complexed with the scaffold protein KSR to promote promigratory E...
Source: Signal Transduction Knowledge Environment - May 18, 2021 Category: Science Authors: Brüggemann, Y., Karajannis, L. S., Stanoev, A., Stallaert, W., Bastiaens, P. I. H. Tags: STKE Research Articles Source Type: news

Distinct nutrient use in tumors
Tumor cells and immune cells in the tumor microenvironment differentially take up nutrients. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 18, 2021 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

Leptin increases GABAergic synaptogenesis through the Rho guanine exchange factor {beta}-PIX in developing hippocampal neurons
Developing hippocampal neurons undergo rapid synaptogenesis in response to neurotrophic signals to form and refine circuit connections. The adipokine leptin is a satiety factor with neurotrophic actions, which potentiates both glutamatergic and GABAergic synaptogenesis in the hippocampus during neonatal development. Brief exposure to leptin enhances GABAA receptor–dependent synaptic currents in hippocampal neurons. Here, using molecular and electrophysiological techniques, we found that leptin increased the surface localization of GABAA receptors and the number of functional GABAergic synapses in hippocampal cultures...
Source: Signal Transduction Knowledge Environment - May 18, 2021 Category: Science Authors: Sahin, G. S., Luis Rodriguez-Llamas, J., Dillon, C., Medina, I., Appleyard, S. M., Gaiarsa, J.-L., Wayman, G. A. Tags: STKE Research Articles Source Type: news

Phosphorylated G{beta} is a directional cue during yeast gradient tracking
Budding yeast cells interpret shallow pheromone gradients from cells of the opposite mating type, polarize their growth toward the pheromone source, and fuse at the chemotropic growth site. We previously proposed a deterministic, gradient-sensing model that explains how yeast cells switch from the intrinsically positioned default polarity site (DS) to the gradient-aligned chemotropic site (CS) at the plasma membrane. Because phosphorylation of the mating-specific Gβ subunit is thought to be important for this process, we developed a biosensor that bound to phosphorylated but not unphosphorylated Gβ and monitored ...
Source: Signal Transduction Knowledge Environment - May 11, 2021 Category: Science Authors: Abdul-Ganiyu, R., Venegas, L. A., Wang, X., Puerner, C., Arkowitz, R. A., Kay, B. K., Stone, D. E. Tags: STKE Research Articles Source Type: news

Cloaked by mutant p53
Mutant p53 takes the STING out of antitumor immunity. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 11, 2021 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

ERK phosphorylation is RAF independent in naïve and activated B cells but RAF dependent in plasma cell differentiation
Members of the RAF family of serine-threonine kinases are intermediates in the mitogen-activated protein kinase and extracellular signal–regulated kinase (MAPK-ERK) signaling pathway, which controls key differentiation processes in B cells. By analyzing mice with B cell–specific deletion of Raf1, Braf, or both, we showed that Raf-1 and B-Raf acted together in mediating the positive selection of pre-B and transitional B cells as well as in initiating plasma cell differentiation. However, genetic or chemical inactivation of RAFs led to increased ERK phosphorylation in mature B cells. ERK activation in the absence...
Source: Signal Transduction Knowledge Environment - May 11, 2021 Category: Science Authors: Scheffler, L., Feicht, S., Babushku, T., Kuhn, L. B., Ehrenberg, S., Frankenberger, S., Lehmann, F. M., Hobeika, E., Jungnickel, B., Baccarini, M., Bornkamm, G. W., Strobl, L. J., Zimber-Strobl, U. Tags: STKE Research Articles Source Type: news

Remodeling of the Homer-Shank interactome mediates homeostatic plasticity
Neurons maintain stable levels of excitability using homeostatic synaptic scaling, which adjusts the strength of a neuron’s postsynaptic inputs to compensate for extended changes in overall activity. Here, we investigated whether prolonged changes in activity affect network-level protein interactions at the synapse. We assessed a glutamatergic synapse protein interaction network (PIN) composed of 380 binary associations among 21 protein members in mouse neurons. Manipulating the activation of cultured mouse cortical neurons induced widespread bidirectional PIN alterations that reflected rapid rearrangements of glutam...
Source: Signal Transduction Knowledge Environment - May 4, 2021 Category: Science Authors: Heavner, W. E., Lautz, J. D., Speed, H. E., Gniffke, E. P., Immendorf, K. B., Welsh, J. P., Baertsch, N. A., Smith, S. E. P. Tags: STKE Research Resources Source Type: news

Structural analysis of the PTEN:P-Rex2 signaling complex reveals how cancer-associated mutations coordinate to hyperactivate Rac1
The dual-specificity phosphatase PTEN functions as a tumor suppressor by hydrolyzing PI(3,4,5)P3 to PI(4,5)P2 to inhibit PI3K-AKT signaling and cellular proliferation. P-Rex2 is a guanine nucleotide exchange factor for Rho GTPases and can be activated by Gβ subunits downstream of G protein–coupled receptor signaling and by PI(3,4,5)P3 downstream of receptor tyrosine kinases. The PTEN:P-Rex2 complex is a commonly mutated signaling node in metastatic cancer. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cellular proliferation. Her...
Source: Signal Transduction Knowledge Environment - May 4, 2021 Category: Science Authors: DAndrea, L., Lucato, C. M., Marquez, E. A., Chang, Y.-G., Civciristov, S., Mastos, C., Lupton, C. J., Huang, C., Elmlund, H., Schittenhelm, R. B., Mitchell, C. A., Whisstock, J. C., Halls, M. L., Ellisdon, A. M. Tags: STKE Research Articles Source Type: news

Polyamines determine dispersal
Monitoring of environmental polyamines controls the dispersal of Vibrio cholerae biofilms. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 4, 2021 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Pinpointing cysteine oxidation sites by high-resolution proteomics reveals a mechanism of redox-dependent inhibition of human STING
Protein function is regulated by posttranslational modifications (PTMs), among which reversible oxidation of cysteine residues has emerged as a key regulatory mechanism of cellular responses. Given the redox regulation of virus-host interactions, the identification of oxidized cysteine sites in cells is essential to understand the underlying mechanisms involved. Here, we present a proteome-wide identification of reversibly oxidized cysteine sites in oxidant-treated cells using a maleimide-based bioswitch method coupled to mass spectrometry analysis. We identified 2720 unique oxidized cysteine sites within 1473 proteins wit...
Source: Signal Transduction Knowledge Environment - April 27, 2021 Category: Science Authors: Zamorano Cuervo, N., Fortin, A., Caron, E., Chartier, S., Grandvaux, N. Tags: STKE Research Articles Source Type: news

Select hyperactivating NLRP3 ligands enhance the TH1- and TH17-inducing potential of human type 2 conventional dendritic cells
The detection of microorganisms and danger signals by pattern recognition receptors on dendritic cells (DCs) and the consequent formation of inflammasomes are pivotal for initiating protective immune responses. Although the activation of inflammasomes leading to secretion of the cytokine IL-1β is typically accompanied by pyroptosis (an inflammatory form of lytic programmed cell death), some cells can survive and exist in a state of hyperactivation. Here, we found that the conventional type 2 DC (cDC2) subset is the major human DC subset that is transcriptionally and functionally poised for inflammasome formation and r...
Source: Signal Transduction Knowledge Environment - April 27, 2021 Category: Science Authors: Hatscher, L., Lehmann, C. H. K., Purbojo, A., Onderka, C., Liang, C., Hartmann, A., Cesnjevar, R., Bruns, H., Gross, O., Nimmerjahn, F., Ivanovic-Burmazovic, I., Kunz, M., Heger, L., Dudziak, D. Tags: STKE Research Articles Source Type: news

Exercising for future generations
A placenta-to-fetus pathway transmits the benefits of maternal exercise on the metabolic health of offspring. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 27, 2021 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation
Production of the proinflammatory cytokine tumor necrosis factor (TNF) must be precisely regulated for effective host immunity without the induction of collateral tissue damage. Here, we showed that TNF production was driven by a spleen-liver axis in a rat model of systemic inflammation induced by bacterial lipopolysaccharide (LPS). Analysis of cytokine expression and secretion in combination with splenectomy and hepatectomy revealed that the spleen generated not only TNF but also factors that enhanced TNF production by the liver, the latter of which accounted for nearly half of the TNF secreted into the circulation. Using...
Source: Signal Transduction Knowledge Environment - April 20, 2021 Category: Science Authors: Fonseca, M. T., Moretti, E. H., Marques, L. M. M., Machado, B. F., Brito, C. F., Guedes, J. T., Komegae, E. N., Vieira, T. S., Festuccia, W. T., Lopes, N. P., Steiner, A. A. Tags: STKE Research Articles Source Type: news

Aging and autoimmunity
Cytoplasmic DNA sensing by the KU complex enhances CD4+ T cell activation and contributes to aging-induced autoimmunity. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 20, 2021 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

CLIC1 and CLIC4 mediate endothelial S1P receptor signaling to facilitate Rac1 and RhoA activity and function
Chloride intracellular channels 1 (CLIC1) and 4 (CLIC4) are expressed in endothelial cells and regulate angiogenic behaviors in vitro, and the expression of Clic4 is important for vascular development and function in mice. Here, we found that CLIC1 and CLIC4 in endothelial cells regulate critical G protein–coupled receptor (GPCR) pathways associated with vascular development and disease. In cultured endothelial cells, we found that CLIC1 and CLIC4 transiently translocated to the plasma membrane in response to sphingosine 1-phosphate (S1P). Both CLIC1 and CLIC4 were essential for mediating S1P-induced activation of th...
Source: Signal Transduction Knowledge Environment - April 20, 2021 Category: Science Authors: Mao, D. Y., Kleinjan, M. L., Jilishitz, I., Swaminathan, B., Obinata, H., Komarova, Y. A., Bayless, K. J., Hla, T., Kitajewski, J. K. Tags: STKE Research Articles Source Type: news

Connect-the-DOT from early stress to depression
Targeting the epigenetic enzyme DOT1L may reverse some behavioral effects of early-life stress. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 13, 2021 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

DDAH2 suppresses RLR-MAVS-mediated innate antiviral immunity by stimulating nitric oxide-activated, Drp1-induced mitochondrial fission
The RIG-I–like receptor (RLR) signaling pathway is pivotal for innate immunity against invading viruses, and dysregulation of this molecular cascade has been linked to various diseases. Here, we identified dimethylarginine dimethylaminohydrolase 2 (DDAH2) as a potent regulator of the RLR-mediated antiviral response in human and mouse. Overexpression of DDAH2 attenuated RLR signaling, whereas loss of DDAH2 function enhanced RLR signaling and suppressed viral replication ex vivo and in mice. Upon viral infection, DDAH2 relocated to mitochondria, where it induced the production of nitric oxide (NO) and the activation of...
Source: Signal Transduction Knowledge Environment - April 13, 2021 Category: Science Authors: Huang, S., Li, Z., Wu, Z., Liu, C., Yu, M., Wen, M., Zhang, L., Wang, X. Tags: STKE Research Articles Source Type: news

mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif
The complex mTORC2 is accepted to be the kinase that controls the phosphorylation of the hydrophobic motif, a key regulatory switch for AGC kinases, although whether mTOR directly phosphorylates this motif remains controversial. Here, we identified an mTOR-mediated phosphorylation site that we termed the TOR interaction motif (TIM; F-x3-F-pT), which controls the phosphorylation of the hydrophobic motif of PKC and Akt and the activity of these kinases. The TIM is invariant in mTORC2-dependent AGC kinases, is evolutionarily conserved, and coevolved with mTORC2 components. Mutation of this motif in Akt1 and PKCβII abolis...
Source: Signal Transduction Knowledge Environment - April 13, 2021 Category: Science Authors: Baffi, T. R., Lorden, G., Wozniak, J. M., Feichtner, A., Yeung, W., Kornev, A. P., King, C. C., Del Rio, J. C., Limaye, A. J., Bogomolovas, J., Gould, C. M., Chen, J., Kennedy, E. J., Kannan, N., Gonzalez, D. J., Stefan, E., Taylor, S. S., Newton, A. C. Tags: STKE Research Articles Source Type: news

ARC unleashes elastase
An antiapoptotic cytoplasmic protein becomes a proapoptotic nuclear protein in diabetes. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 6, 2021 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news