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PubMed2002

Multiple signaling pathways leading to the activation of interferon regulatory factor 3.

Virus infection of susceptible cells activates multiple signaling pathways that orchestrate the activation of genes, such as cytokines, involved in the antiviral and innate immune response. Among the kinases induced are the mitogen-activated protein (MAP) kinases, Jun-amino terminal kinases (JNK) and p38, the IkappaB kinase (IKK) and DNA-PK. In addition, virus infection also activates an uncharacterized VAK responsible for the C-terminal phosphorylation and subsequent activation of interferon regulatory factor 3 (IRF-3). Virus-mediated activation of IRF-3 through VAK is dependent on viral entry and transcription, since replication deficient virus failed to induce IRF-3 activity. The pathways leading to VAK activation are not well characterized, but IRF-3 appears to represent a novel cellular detection pathway that recognizes viral nucleocapsid (N) structure. Recently, the range of inducers responsible for IRF-3 activation has increased. In addition to virus infection, recognition of bacterial infection mediated through lipopolysaccharide by Toll-like receptor 4 has also been reported. Furthermore, MAP kinase kinase kinase (MAP KKK)-related pathways and DNA-PK induce N-terminal phosphorylation of IRF-3. This review summarizes recent observations in the identification of novel signaling pathways leading to IRF-3 activation.

Animals↗
PubMed2004

Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways.

The effects of estrogens, particularly 17beta-estradiol (E2), are mediated by estrogen receptor alpha (ERalpha) and ERbeta. Upon binding to E2, ERs homo- and heterodimerize when coexpressed. The ER dimer then regulates the transcription of target genes through estrogen responsive element (ERE)-dependent and -independent pathways that constitute genomic estrogen signaling. Although ERalpha and ERbeta have similar ERE and E2 binding properties, they display different transregulatory capacities in both ERE-dependent and -independent signaling pathways. It is therefore likely that the heterodimerization provides novel functions to ERs by combining distinct properties of the contributing partners. The elucidation of the role of the ER heterodimer is critical for the understanding of physiology and pathophysiology of E2 signaling. However, differentially determining target gene responses during cosynthesis of ER subtypes is difficult, since dimers formed are a heterogeneous population of homo- and heterodimers. To circumvent the pivotal dimerization step in ER action and hence produce a homogeneous ER heterodimer population, we utilized a genetic fusion strategy. We joined the cDNAs of ERalpha and/or ERbeta to produce single-chain ERs to simulate the ER homo- and heterodimers. The fusion ERs interacted with ERE and E2 in a manner similar to that observed with the ER dimers. The homofusion receptors mimicked the functions of the parent ER dimers in the ERE-dependent and -independent pathways in transfected mammalian cells, whereas heterofusion receptors emulated the transregulatory properties of the ERalpha dimer. These results suggest that ERalpha is the functionally dominant partner in the ERalpha/beta heterodimer.

Animals↗
PubMed1999

Interaction of glutamic-acid-rich proteins with the cGMP signalling pathway in rod photoreceptors.

The assembly of signalling molecules into macromolecular complexes (transducisomes) provides specificity, sensitivity and speed in intracellular signalling pathways. Rod photoreceptors in the eye contain an unusual set of glutamic-acid-rich proteins (GARPs) of unknown function. GARPs exist as two soluble forms, GARP1 and GARP2, and as a large cytoplasmic domain (GARP' part) of the beta-subunit of the cyclic GMP-gated channel. Here we identify GARPs as multivalent proteins that interact with the key players of cGMP signalling, phosphodiesterase and guanylate cyclase, and with a retina-specific ATP-binding cassette transporter (ABCR), through four, short, repetitive sequences. In electron micrographs, GARPs are restricted to the rim region and incisures of discs in close proximity to the guanylate cyclase and ABCR, whereas the phosphodiesterase is randomly distributed. GARP2, the most abundant splice form, associates more strongly with light-activated than with inactive phosphodiesterase, and GARP2 potently inhibits phosphodiesterase activity. Thus, the GARPs organize a dynamic protein complex near the disc rim that may control cGMP turnover and possibly other light-dependent processes. Because there are no similar GARPs in cones, we propose that GARPs may prevent unnecessary cGMP turnover during daylight, when rods are held in saturation by the relatively high light levels.

ATP-Binding Cassette Transporters↗
PubMed2006

Induction of the myofibroblastic phenotype in human gingival fibroblasts by transforming growth factor-beta1: role of RhoA-ROCK and c-Jun N-terminal kinase signaling pathways.

BACKGROUND AND OBJECTIVES: Myofibroblastic differentiation is an important event in gingival wound healing and chronic inflammation. Transforming growth factor-beta 1 (TGF-beta1) is a potent growth factor that has been implicated in this process. Gingival myofibroblasts have an increased ability to remodel the extracellular matrix and this feature has been associated with changes in the distribution of F-actin and the expression of the myofibroblast marker alpha-smooth muscle actin. In the present study we have analyzed the role of TGF-beta1 and the signaling routes activated by this factor in the cytoskeletal changes that characterize the myofibroblastic differentiation process in human gingival fibroblasts. MATERIALS AND METHODS: The signalling pathways involved in myofibroblastic differentiation were studied in primary cultures of human gingival fibroblasts using several signal transduction inhibitors. RhoA activation was analyzed through a pull-down assay. Distribution of focal adhesions and actin cytoskeleton was assessed by means of immunofluorescence and western blot. A cell adhesion assay was performed in TGF-beta1-stimulated cells. Smooth muscle actin expression was studied through western blot and immunofluorescence. c-Jun N-terminal kinase phosphorylation was assessed through western blot. RESULTS: Our observations show that TGF-beta1 activated the GTPase RhoA, a key regulator of the actin cytoskeleton. As a consequence of this event, this growth factor stimulated the generation of actin stress fibers and the reinforcement of vinculin-enriched focal adhesions. These responses were blocked after inhibiting ROCK, the main target of RhoA activation. TGF-beta1 also stimulated the adhesion of fibroblasts over fibronectin, an extracellular matrix molecule involved in myofibroblastic differentiation. Finally, induction of the myofibroblast marker alpha-smooth muscle actin by TGF-beta1 was abolished by the c-Jun N-terminal protein kinase inhibitor SP600125, suggesting a role for this signaling pathway during the induction of this phenotype. CONCLUSIONS: We propose that TGF-beta1 may promote the differentiation of myofibroblasts through the stimulation of cell spreading and adhesion, the reinforcement of focal adhesions, the maturation of the actin cytoskeleton, and the induction of alpha-smooth muscle actin. Activity of RhoA-ROCK and c-Jun N-terminal protein kinase signaling pathways are probably involved in these cellular events.

Actins↗
PubMed2004

Herpes simplex virus 1 gene products occlude the interferon signaling pathway at multiple sites.

Earlier studies have shown that herpes simplex virus 1 (HSV-1) blocks the interferon response pathways, at least at two sites, by circumventing the effects of activation of protein kinase R by double-stranded RNA and interferon and through the degradation of promyelocytic leukemia protein (PML) since interferon has no antiviral effects in PML(-/-) cells. Here we report on two effects of viral genes on other sites of the interferon signaling pathway. (i) In infected cells, Jak1 kinase associated with interferon receptors and Stat2 associated with the interferon signaling pathway rapidly disappear from infected cells. The level of interferon alpha receptor is also reduced, albeit less drastically at times after 4 h postinfection. Other members of the Stat family of proteins were either decreased in amount or posttranslationally processed in a manner different from those of mock-infected cells. The decrease in the levels of Jak1 and Stat2 may account for the decrease in the formation of complexes consisting of Stat1 or ISGF3 and DNA sequences containing the interferon-stimulated response elements after exposure to interferon. (ii) The disappearance of Jak1 and Stat2 was related at least in part to the function of the virion host shutoff protein, the product of the viral U(L)41 gene. Consistent with this observation, a mutant lacking the U(L)41 gene and treated with interferon produced lesser amounts of a late protein (U(L)38) than the wild-type parent. We conclude that HSV-1 blocks the interferon signaling pathways at several sites.

Animals↗
PubMed2006

TGF-beta1/SMAD signaling pathway mediates p53-dependent apoptosis in hepatoma cell lines.

OBJECTIVE: To determine whether transforming growth factor betal (TGF-beta1)/Smad signaling pathway mediates p53-dependent apoptosis in hepatoma cell lines. METHODS: Three human hepatic carcinoma cell lines, HepG2, Huh-7, and Hep3B, were used in this study. TGF-beta1-induced apoptosis in hepatic carcinoma cell lines was analyzed using TUNEL assay. For identifying the mechanism of apoptosis induced by TGF-beta1, cell lines were transfected with a TGF-beta1-inducible luciferase reportor plasmid containing Smad4 binding elements. After transfection, cells were treated with TGF-beta1, then assayed for luciferase activity. RESULTS: The apoptosis rate of HepG2 cell lines (48.51% +/- 8.21%) was significantly higher than control (12.72% +/- 2.18%, P <0.05). But TGF-beta1 was not able to induce apoptosis of Huh-7 and Hep3B cell lines. The relative luciferase activity of TGF-beta1-treated HepG2 cell lines (4.38) was significantly higher than control (1.00, P < 0.05). But the relative luciferase activity of TGF-beta1-treated Huh-7 and Hep3B cell lines less increased compared with control. CONCLUSIONS: HepG2 cells seem to be highly susceptible to TGF-beta1-induced apoptosis compared with Hep3B and Huh-7 cell lines. Smad4 is a central mediator of TGF-beta1 signaling transdution pathway. TGF-beta1/Smad signaling pathway might mediate p53-dependent apoptosis in hepatoma cell lines.

Apoptosis↗
PubMed2005

The zebrafish mutants dre, uki, and lep encode negative regulators of the hedgehog signaling pathway.

Proliferation is one of the basic processes that control embryogenesis. To identify factors involved in the regulation of proliferation, we performed a zebrafish genetic screen in which we used proliferating cell nuclear antigen (PCNA) expression as a readout. Two mutants, hu418B and hu540A, show increased PCNA expression. Morphologically both mutants resembled the dre (dreumes), uki (ukkie), and lep (leprechaun) mutant class and both are shown to be additional uki alleles. Surprisingly, although an increased size is detected of multiple structures in these mutant embryos, adults become dwarfs. We show that these mutations disrupt repressors of the Hedgehog (Hh) signaling pathway. The dre, uki, and lep loci encode Su(fu) (suppressor of fused), Hip (Hedgehog interacting protein), and Ptc2 (Patched2) proteins, respectively. This class of mutants is therefore unique compared to previously described Hh mutants from zebrafish genetic screens, which mainly show loss of Hh signaling. Furthermore, su(fu) and ptc2 mutants have not been described in vertebrate model systems before. Inhibiting Hh activity by cyclopamine rescues uki and lep mutants and confirms the overactivation of the Hh signaling pathway in these mutants. Triple uki/dre/lep mutants show neither an additive increase in PCNA expression nor enhanced embryonic phenotypes, suggesting that other negative regulators, possibly Ptc1, prevent further activation of the Hh signaling pathway. The effects of increased Hh signaling resulting from the genetic alterations in the uki, dre, and lep mutants differ from phenotypes described as a result of Hh overexpression and therefore provide additional insight into the role of Hh signaling during vertebrate development.

Animals↗
PubMed2004

Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 envelope glycoprotein gB induces the integrin-dependent focal adhesion kinase-Src-phosphatidylinositol 3-kinase-rho GTPase signal pathways and cytoskeletal rearrangements.

Human herpesvirus 8 (HHV-8; Kaposi's sarcoma-associated herpesvirus) envelope glycoprotein gB possesses an RGD motif, interacts with alpha 3 beta 1 integrin, and uses it as one of the entry receptors. HHV-8 induces the integrin-dependent focal adhesion kinase (FAK), a critical step in the outside-in signaling pathways necessary for the subsequent phosphorylation of other cellular kinases, cytoskeletal rearrangements, and other functions. As an initial step toward deciphering the role of HHV-8 gB-integrin interaction in infection, signal pathways induced by gB were examined. A truncated form of gB without the transmembrane and carboxyl domains (gB Delta TM), a gB Delta TM mutant form (gB Delta TM-RGA) with an RGD-to-RGA mutation, and inhibitors of cellular kinases were used. HHV-8 gB Delta TM, but not gB Delta TM-RGA, induced FAK phosphorylation in target cells, which was in part dependent on the presence of alpha 3 beta 1 integrin. FAK was critical for the subsequent phosphorylation of Src by gB Delta TM, and Src induction was essential for the phosphorylation of phosphatidylinositol 3-kinase (PI-3K). HHV-8 gB Delta TM-induced PI-3K was essential for the induction of RhoA and Cdc42 Rho GTPases that was accompanied by the cytoskeletal rearrangements. These gB-induced morphological changes were inhibited by the PI-3K inhibitors. Ezrin, one of the essential elements required to cross-link the actin cytoskeleton with the plasma membrane and to induce the morphological changes, was induced by the Rho GTPases. Inhibition of cellular tyrosine kinases by the brief treatment of cells with 4',5,7-trihydroxyisoflavone (genistein) blocked the entry of HHV-8 into target cells. These findings suggest that, independently of other viral glycoproteins and via its RGD motif, HHV-8 gB induces integrin-dependent pre-existing FAK-Src-PI-3K-Rho GTPase kinases. Since these signal pathways play vital roles in host cell endocytosis and movement of particulate materials in the cytoplasm, the early stages of HHV-8 gB interaction with host cells may provide a very conducive environment for the successful infection of target cells.

Animals↗
PubMed2006

Multiple role of histamine H1-receptor-PKC-MAPK signalling pathway in histamine-stimulated nerve growth factor synthesis and secretion.

Histamine is a potent stimulator of nerve growth factor (NGF) production in the central nerve system and in the periphery as well. In this review, the biochemical mechanisms of histamine-stimulated NGF synthesis and secretion, and interactions between histamine, interleukin-1beta, and interleukin-6 are discussed. The main signalling pathway, involved in the stimulation of NGF production by histamine, includes activation of histamine H(1)-receptor, stimulation of Ca(2+)-dependent protein kinase C and mitogen-activated protein kinase. The same signalling pathway is involved in the interactions between histamine, interleukin-1beta, and interleukin-6, where NGF secretion is amplified. Whereas histamine and interleukin-1beta cause additive stimulatory effect on NGF secretion, interaction between histamine and interleukin-6 causes a long-term synergism. Thus, activation of histamine H(1)-receptor-protein kinase C-mitogen-activated protein kinase signalling pathway plays a crucial role not only in the direct stimulation of NGF secretion by histamine, but also in the indirect stimulation via different types of interactions between histamine, interleukin-1beta, and interleukin-6, which may have important therapeutic implications in modulation of NGF production.

Animals↗
PubMed2000

Expression of activated MAP kinase in Xenopus laevis embryos: evaluating the roles of FGF and other signaling pathways in early induction and patterning.

FGF signaling has been implicated in germ layer formation and axial determination. An antibody specific for the activated form of mitogen-activated protein kinase (MAPK) was used to monitor FGF signaling in vivo during early Xenopus development. Activation of MAPK in young embryos is abolished by injection of a dominant negative FGF receptor (XFD) RNA, suggesting that MAPK is activated primarily by FGF in this context. A transition from cytoplasmic to nuclear localization of activated MAPK occurs in morula/blastula stage embryo animal and marginal zones coinciding with the proposed onset of mesodermal competence. Activated MAPK delineates the region of the dorsal marginal zone before blastopore formation and persists in this region during gastrulation, indicating an early role for FGF signaling in dorsal mesoderm. Activated MAPK was also found in posterior neural tissue from late gastrulation onward. Inhibition of FGF signaling does not block posterior neural gene expression (HoxB9) or activation of MAPK; however, inhibition of FGF signaling does cause a statistically significant decrease in the level of activated MAPK. These results point toward the involvement of other receptor tyrosine kinase signaling pathways in posterior neural patterning.

Active Transport, Cell Nucleus↗
PubMed1996

Interleukin-4 gene expression in activated human T lymphocytes is regulated by the cyclic adenosine monophosphate-dependent signaling pathway.

In the present study, we have investigated the involvement of the cyclic adenosine monophosphate (cAMP)-dependent signaling pathway on interleukin-4 (IL-4) gene expression in freshly isolated human T lymphocytes. 2'-0-dibutyryl cAMP (db-cAMP) and prostaglandin E2 (PGE2) were used to directly and indirectly activate the protein kinase A pathway. Northern analysis showed that concanavalin A (Con A)-, anti-CD3 (alpha CD3)-, or anti-CD3 plus anti-CD28 (alpha CD3/alpha CD28)-induced accumulation of IL-4 mRNA was inhibited by db-cAMP (10(-3) mol/L). Db-cAMP showed a steep dose-dependent inhibition; concentrations < or = 10(-4) mol/L did not affect IL-4 mRNA accumulation. In contrast, GM-CSF mRNA expression showed a wider dose-dependent range; 10(-5) mol/L db-cAMP still affected GM-CSF accumulation. PGE2 inhibited the Con A- and alpha CD3/alpha CD28-induced accumulation of IL-4 mRNA in a dose-dependent fashion. Con A-induced IL-4 mRNA was inhibited by 10(-4) to 10(-7) mol/L PGE2; alpha CD3/alpha CD28-induced IL-4 mRNA was inhibited by 10(-5) to 10(-8) mol/L PGE2. Nuclear run-on experiments showed that the inhibitory effects of db-cAMP and PGE2 were accomplished at transcriptional level in Con A-activated T cells, whereas changes at transcriptional and posttranscriptional level were involved in alpha CD3/alpha CD28-activated T lymphocytes. In contrast to Con A and alpha CD3/alpha CD28 activation, phorbol myristate acetate plus A23187-induced IL-4 mRNA expression was insensitive to the inhibitory effect of db-cAMP and PGE2. Moreover, it appeared that the sensitivity for cAMP-mediated downregulation could not be blocked by stimulation T lymphocytes with alpha CD3/alpha CD28 in the presence of IL-2, IL-7, IL-10, IL-12, or a combination of these cytokines. Finally, it was shown that, in accordance with the mRNA studies, db-cAMP and PGE2 suppressed the IL-4 secretion in Con A- and alpha CD3/alpha CD28-activated T cells. In conclusion, these data show that IL-4 expression is negatively regulated by the protein kinase A-dependent signaling pathway by transcriptional and posttranscriptional mechanisms that depend on costimulatory signals.

Antibodies, Monoclonal↗
PubMed2006

Charting protein complexes, signaling pathways, and networks in the immune system.

Systematic deciphering of protein-protein interactions has the potential to generate comprehensive and instructive signaling networks and to fuel new therapeutic and diagnostic strategies. Here, we describe how recent advances in high-throughput proteomic technologies, involving biochemical purification methods and mass spectrometry analysis, can be applied systematically to the characterization of protein complexes and the computation of molecular networks. The networks obtained form the basis for further functional analyses, such as knockdown by RNA interference, ultimately leading to the identification of nodes that represent candidate targets for pharmacological exploitation. No individual experimental approach can accurately elucidate all critical modulatory components and biological aspects of a signaling network. Such functionally annotated protein-protein interaction networks, however, represent an ideal platform for the integration of additional datasets. By providing links between molecules, they also provide links to all previous observations associated with these molecules, be they of genetic, pharmacological, or other origin. As exemplified here by the analysis of the tumor necrosis factor (TNF)-alpha/nuclear factor-kappaB (NF-kappaB) signaling pathway, the approach is applicable to any mammalian cellular signaling pathway in the immune system.

Animals↗
PubMed1998

Cellular interactions in the thymus regulate the protein kinase C signaling pathway.

We provide evidence that thymocytes receive signals from the thymic microenvironment which regulate the protein kinase C (PKC) signaling pathway. Thus, phorbol 12-myristate 13-acetate (PMA) causes a PKC-dependent down-regulation of CD4 expression and induces apoptosis in isolated thymocytes but has little effect on thymocytes maintained within intact thymic lobes or in reaggregate lobes containing purified thymocytes with either thymic or non-thymic stromal cells. Moreover, compact pellets of thymocytes alone are protected from the effects of PMA. This protection is maintained when the compacted thymocytes are rigorously depleted of MHC class II-expressing cells. We conclude that signals arising from thymocyte-thymocyte contact control the utilization of the PKC cascade. These observations have implications for thymocyte signaling in general as well as for the interpretation of studies carried out on thymocyte suspensions.

Animals↗
PubMed2003

The same cellular signaling pathways mediate survival in sensory neurons that switch their trophic requirements during development.

A distinct subpopulation of rat dorsal root sensory (DRG) neurons, termed P-neurons, switch their trophic requirements for survival during development from nerve growth factor (NGF) at embryonic stages to basic fibroblast growth factor (bFGF) just after birth. We investigated in cultured P-neurons the intracellular signaling pathways mediating survival before and after this switch. The NGF-induced survival was completely blocked by either wortmannin (100 nM) or PD98059 (25-50 nM), which selectively inhibit the phosphatidylinositol 3-kinase-AKT (PI3 kinase-AKT) and mitogen-activated kinase kinase extracellular regulated kinase (MEK-ERKs) pathways, respectively. NGF activated AKT and ERKs in single embryonic P-neurons, as assayed by immunofluorescence of phosphorylated proteins. In concordance with the survival assays, wortmannin and PD98059 blocked AKT and ERKs activation, respectively. Following the trophic switch, bFGF used the same signaling pathways to promote survival of post-natal P-neurons, as either wortmannin or PD98059 blocked its effect. Also, bFGF activated AKT and ERKs in single P-neurons, and this activation was blocked by the same inhibitors. These results strongly suggest that both pathways concurrently mediate the action of NGF and bFGF during embryonic and post-natal periods, respectively. Thus, we report the novel result that the switch in trophic requirements occurs with conservation of the signaling pathways mediating survival.

Androstadienes↗
PubMed2004

Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway.

The large protein kinases, ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR), orchestrate DNA damage checkpoint pathways. In budding yeast, ATM and ATR homologs are encoded by TEL1 and MEC1, respectively. The Mre11 complex consists of two highly related proteins, Mre11 and Rad50, and a third protein, Xrs2 in budding yeast or Nbs1 in mammals. The Mre11 complex controls the ATM/Tel1 signaling pathway in response to double-strand break (DSB) induction. We show here that the Mre11 complex functions together with exonuclease 1 (Exo1) in activation of the Mec1 signaling pathway after DNA damage and replication block. Mec1 controls the checkpoint responses following UV irradiation as well as DSB induction. Correspondingly, the Mre11 complex and Exo1 play an overlapping role in activation of DSB- and UV-induced checkpoints. The Mre11 complex and Exo1 collaborate in producing long single-stranded DNA (ssDNA) tails at DSB ends and promote Mec1 association with the DSBs. The Ddc1-Mec3-Rad17 complex associates with sites of DNA damage and modulates the Mec1 signaling pathway. However, Ddc1 association with DSBs does not require the function of the Mre11 complex and Exo1. Mec1 controls checkpoint responses to stalled DNA replication as well. Accordingly, the Mre11 complex and Exo1 contribute to activation of the replication checkpoint pathway. Our results provide a model in which the Mre11 complex and Exo1 cooperate in generating long ssDNA tracts and thereby facilitate Mec1 association with sites of DNA damage or replication block.

Cell Cycle Proteins↗
PubMed2002

Light-signalling pathways leading to the co-ordinated expression of HEMA1 and Lhcb during chloroplast development in Arabidopsis thaliana.

During de-etiolation, the co-ordinated synthesis of chlorophyll and the chlorophyll a/b-binding proteins is critical to the development of functional light-harvesting complexes. To understand how this co-ordination is achieved, we have made a detailed study of the light-regulated signalling pathways mediating the expression of the HEMA1 and Lhcb genes encoding glutamyl-tRNA reductase, the first committed enzyme of 5-aminolaevulinic acid formation, and chlorophyll a/b-binding proteins, respectively. To do this, we have screened 7 photoreceptor and 12 light-signalling mutants of Arabidopsis thaliana L. for induction of HEMA1 and Lhcb expression in continuous red, far-red and blue light and following a red pulse. We have categorised these mutants into two groups. The phyA, phyB, phyAphyB, cry1, cry2, cop1, det1, poc1, eid1, and far1 mutations lead to diverse effects on the light regulation of HEMA1, but affect Lhcb expression to a similar degree. The hy1, hy2, hy5, fin219, fhy1, fhy3, spa1, ndpk2, and pat1 mutants also affect light regulation of both HEMA1 and Lhcb expression, but with differences in the relative magnitude of the two responses. The fhy1 and fhy3 mutants show the most significant differences in light regulation between the two genes, with both showing a strong inhibition of HEMA1 expression under continuous red light. These results demonstrate that co-ordinated regulation of HEMA1 and Lhcb is largely achieved through parallel light regulation mediated by shared phytochrome- and cryptochrome-signalling pathways. However, glutamyl-tRNA reductase is also required for the synthesis of other tetrapyrroles and this dual role may account for the observed differences in these light-signalling pathways.

Aldehyde Oxidoreductases↗
PubMed2024

Convergence on CaMK4: A Key Modulator of Autism-Associated Signaling Pathways in Neurons.

Although the precise underlying cause(s) of autism spectrum disorder remain unclear, more than 1000 rare genetic variations are associated with the condition. For many people living with profound autism, this genetic heterogeneity has impeded the identification of common biological targets for therapy development for core and comorbid traits that include significant impairments in social communication and repetitive and restricted behaviors. A substantial number of genes associated with autism encode proteins involved in signal transduction and synaptic transmission that are critical for brain development and function. CAMK4 is an emerging risk gene for autism spectrum disorder that encodes the CaMK4 (calcium/calmodulin-dependent protein kinase 4) enzyme. CaMK4 is a key component of a Ca2+-activated signaling pathway that regulates neurodevelopment and synaptic plasticity. In this review, we discuss 3 genetic variants of CAMK4 found in individuals with hyperkinetic movement disorder and comorbid neurological symptoms including autism spectrum disorder that are likely pathogenic with monogenic effect. We also comment on 4 other genetic variations in CAMK4 that show associations with autism spectrum disorder, as well as 12 examples of autism-associated variations in other genes that impact CaMK4 signaling pathways. Finally, we highlight 3 environmental risk factors that impact CaMK4 signaling based on studies of preclinical models of autism and/or clinical cohorts. Overall, we review molecular, genetic, physiological, and environmental evidence that suggest that defects in the CaMK4 signaling pathway may play an important role in a common autism pathogenesis network across numerous patient groups, and we propose CaMK4 as a potential therapeutic target.

Humans↗