Genes and Development

The Gal3p transducer of the GAL regulon interacts with the Gal80p repressor in its ligand-induced closed conformation.

Publication Date: 2012 Feb 1 PMID: 22302941
Authors: Lavy, T. - Kumar, P. R. - He, H. - Joshua-Tor, L.
Journal: Genes Dev

A wealth of genetic information and some biochemical analysis have made the GAL regulon of the yeast Saccharomyces cerevisiae a classic model system for studying transcriptional activation in eukaryotes. Galactose induces this transcriptional switch, which is regulated by three proteins: the transcriptional activator Gal4p, bound to DNA; the repressor Gal80p; and the transducer Gal3p. We showed previously that NADP appears to act as a trigger to kick the repressor off the activator. Sustained activation involves a complex of the transducer Gal3p and Gal80p mediated by galactose and ATP. We solved the crystal structure of the complex of Gal3p-Gal80p with alpha-D-galactose and ATP to 2.1 A resolution. The interaction between the proteins occurs only when Gal3p is in a "closed" state induced by ligand binding. The structure of the complex provides a rationale for the phenotypes of several well-known Gal80p and Gal3p mutants as well as the lack of galactokinase activity of Gal3p.

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A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting.

Publication Date: 2012 Feb 1 PMID: 22302940
Authors: Hugo, S. E. - Cruz-Garcia, L. - Karanth, S. - Anderson, R. M. - Stainier, D. Y. - Schlegel, A.
Journal: Genes Dev

To find new genes that influence liver lipid mass, we performed a genetic screen for zebrafish mutants with hepatic steatosis, a pathological accumulation of fat. The red moon (rmn) mutant develops hepatic steatosis as maternally deposited yolk is depleted. Conversely, hepatic steatosis is suppressed in rmn mutants by adequate nutrition. Adult rmn mutants show increased liver neutral lipids and induction of hepatic lipid biosynthetic genes when fasted. Positional cloning of the rmn locus reveals a loss-of-function mutation in slc16a6a (solute carrier family 16a, member 6a), a gene that we show encodes a transporter of the major ketone body beta-hydroxybutyrate. Restoring wild-type zebrafish slc16a6a expression or introducing human SLC16A6 in rmn mutant livers rescues the mutant phenotype. Radiotracer analysis confirms that loss of Slc16a6a function causes diversion of liver-trapped ketogenic precursors into triacylglycerol. Underscoring the importance of Slc16a6a to normal fasting physiology, previously fed rmn mutants are more sensitive to death by starvation than are wild-type larvae. Our unbiased, forward genetic approach has found a heretofore unrecognized critical step in fasting energy metabolism: hepatic ketone body transport. Since beta-hydroxybutyrate is both a major fuel and a signaling molecule in fasting, the discovery of this transporter provides a new direction for modulating circulating levels of ketone bodies in metabolic diseases.

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FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis.

Publication Date: 2012 Feb 1 PMID: 22302939
Authors: Fisher, F. M. - Kleiner, S. - Douris, N. - Fox, E. C. - Mepani, R. J. - Verdeguer, F. - Wu, J. - Kharitonenkov, A. - Flier, J. S. - Maratos-Flier, E. - Spiegelman, B. M.
Journal: Genes Dev

Certain white adipose tissue (WAT) depots are readily able to convert to a "brown-like" state with prolonged cold exposure or exposure to beta-adrenergic compounds. This process is characterized by the appearance of pockets of uncoupling protein 1 (UCP1)-positive, multilocular adipocytes and serves to increase the thermogenic capacity of the organism. We show here that fibroblast growth factor 21 (FGF21) plays a physiologic role in this thermogenic recruitment of WATs. In fact, mice deficient in FGF21 display an impaired ability to adapt to chronic cold exposure, with diminished browning of WAT. Adipose-derived FGF21 acts in an autocrine/paracrine manner to increase expression of UCP1 and other thermogenic genes in fat tissues. FGF21 regulates this process, at least in part, by enhancing adipose tissue PGC-1alpha protein levels independently of mRNA expression. We conclude that FGF21 acts to activate and expand the thermogenic machinery in vivo to provide a robust defense against hypothermia.

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Dietary obesity-associated Hif1alpha activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system.

Publication Date: 2012 Feb 1 PMID: 22302938
Authors: Krishnan, J. - Danzer, C. - Simka, T. - Ukropec, J. - Walter, K. M. - Kumpf, S. - Mirtschink, P. - Ukropcova, B. - Gasperikova, D. - Pedrazzini, T. - Krek, W.
Journal: Genes Dev

Dietary obesity is a major factor in the development of type 2 diabetes and is associated with intra-adipose tissue hypoxia and activation of hypoxia-inducible factor 1alpha (HIF1alpha). Here we report that, in mice, Hif1alpha activation in visceral white adipocytes is critical to maintain dietary obesity and associated pathologies, including glucose intolerance, insulin resistance, and cardiomyopathy. This function of Hif1alpha is linked to its capacity to suppress beta-oxidation, in part, through transcriptional repression of sirtuin 2 (Sirt2) NAD(+)-dependent deacetylase. Reduced Sirt2 function directly translates into diminished deacetylation of PPARgamma coactivator 1alpha (Pgc1alpha) and expression of beta-oxidation and mitochondrial genes. Importantly, visceral adipose tissue from human obese subjects is characterized by high levels of HIF1alpha and low levels of SIRT2. Thus, by negatively regulating the Sirt2-Pgc1alpha regulatory axis, Hif1alpha negates adipocyte-intrinsic pathways of fatty acid catabolism, thereby creating a metabolic state supporting the development of obesity.

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Structural basis of agrin-LRP4-MuSK signaling.

Publication Date: 2012 Feb 1 PMID: 22302937
Authors: Zong, Y. - Zhang, B. - Gu, S. - Lee, K. - Zhou, J. - Yao, G. - Figueiredo, D. - Perry, K. - Mei, L. - Jin, R.
Journal: Genes Dev

Synapses are the fundamental units of neural circuits that enable complex behaviors. The neuromuscular junction (NMJ), a synapse formed between a motoneuron and a muscle fiber, has contributed greatly to understanding of the general principles of synaptogenesis as well as of neuromuscular disorders. NMJ formation requires neural agrin, a motoneuron-derived protein, which interacts with LRP4 (low-density lipoprotein receptor-related protein 4) to activate the receptor tyrosine kinase MuSK (muscle-specific kinase). However, little is known of how signals are transduced from agrin to MuSK. Here, we present the first crystal structure of an agrin-LRP4 complex, consisting of two agrin-LRP4 heterodimers. Formation of the initial binary complex requires the z8 loop that is specifically present in neuronal, but not muscle, agrin and that promotes the synergistic formation of the tetramer through two additional interfaces. We show that the tetrameric complex is essential for neuronal agrin-induced acetylcholine receptor (AChR) clustering. Collectively, these results provide new insight into the agrin-LRP4-MuSK signaling cascade and NMJ formation and represent a novel mechanism for activation of receptor tyrosine kinases.

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Tel1ATM and Rad3ATR phosphorylate the telomere protein Ccq1 to recruit telomerase and elongate telomeres in fission yeast.

Publication Date: 2012 Feb 1 PMID: 22302936
Authors: Yamazaki, H. - Tarumoto, Y. - Ishikawa, F.
Journal: Genes Dev

In fission yeast, the DNA damage sensor kinases Tel1(ATM) and Rad3(ATR) exist at telomeres and are required for telomere maintenance, but the biological role they play at telomeres is not known. Here we show that the telomere protein Ccq1 is phosphorylated at Thr 93 (threonine residue at amino acid 93) by Tel1(ATM) and Rad3(ATR) both in vitro and in vivo. A ccq1 mutant in which alanine was substituted for Thr 93 failed to recruit telomerase to telomeres and showed gradual shortening of telomeres. These results indicate that the direct phosphorylation of Ccq1 Thr 93 by Tel1 and Rad3 is involved in the recruitment of telomerase to elongate telomeres.

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NF-kappaB, the first quarter-century: remarkable progress and outstanding questions.

Publication Date: 2012 Feb 1 PMID: 22302935
Authors: Hayden, M. S. - Ghosh, S.
Journal: Genes Dev

The ability to sense and adjust to the environment is crucial to life. For multicellular organisms, the ability to respond to external changes is essential not only for survival but also for normal development and physiology. Although signaling events can directly modify cellular function, typically signaling acts to alter transcriptional responses to generate both transient and sustained changes. Rapid, but transient, changes in gene expression are mediated by inducible transcription factors such as NF-kappaB. For the past 25 years, NF-kappaB has served as a paradigm for inducible transcription factors and has provided numerous insights into how signaling events influence gene expression and physiology. Since its discovery as a regulator of expression of the kappa light chain gene in B cells, research on NF-kappaB continues to yield new insights into fundamental cellular processes. Advances in understanding the mechanisms that regulate NF-kappaB have been accompanied by progress in elucidating the biological significance of this transcription factor in various physiological processes. NF-kappaB likely plays the most prominent role in the development and function of the immune system and, not surprisingly, when dysregulated, contributes to the pathophysiology of inflammatory disease. As our appreciation of the fundamental role of inflammation in disease pathogenesis has increased, so too has the importance of NF-kappaB as a key regulatory molecule gained progressively greater significance. However, despite the tremendous progress that has been made in understanding the regulation of NF-kappaB, there is much that remains to be understood. In this review, we highlight both the progress that has been made and the fundamental questions that remain unanswered after 25 years of study.

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Suppression of progenitor differentiation requires the long noncoding RNA ANCR.

Publication Date: 2012 Feb 2 PMID: 22302877
Authors: Kretz, M. - Webster, D. E. - Flockhart, R. J. - Lee, C. S. - Zehnder, A. - Lopez-Pajares, V. - Qu, K. - Zheng, G. X. - Chow, J. - Kim, G. E. - Rinn, J. L. - Chang, H. Y. - Siprashvili, Z. - Khavari, P. A.
Journal: Genes Dev

Long noncoding RNAs (lncRNAs) regulate diverse processes, yet a potential role for lncRNAs in maintaining the undifferentiated state in somatic tissue progenitor cells remains uncharacterized. We used transcriptome sequencing and tiling arrays to compare lncRNA expression in epidermal progenitor populations versus differentiating cells. We identified ANCR (anti-differentiation ncRNA) as an 855-base-pair lncRNA down-regulated during differentiation. Depleting ANCR in progenitor-containing populations, without any other stimuli, led to rapid differentiation gene induction. In epidermis, ANCR loss abolished the normal exclusion of differentiation from the progenitor-containing compartment. The ANCR lncRNA is thus required to enforce the undifferentiated cell state within epidermis.

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Endocrine fibroblast growth factors 15/19 and 21: from feast to famine.

Publication Date: 2012 Feb 2 PMID: 22302876
Authors: Potthoff, M. J. - Kliewer, S. A. - Mangelsdorf, D. J.
Journal: Genes Dev

We review the physiology and pharmacology of two atypical fibroblast growth factors (FGFs)-FGF15/19 and FGF21-that can function as hormones. Both FGF15/19 and FGF21 act on multiple tissues to coordinate carbohydrate and lipid metabolism in response to nutritional status. Whereas FGF15/19 is secreted from the small intestine in response to feeding and has insulin-like actions, FGF21 is secreted from the liver in response to extended fasting and has glucagon-like effects. FGF21 also acts in an autocrine fashion in several tissues, including adipose. The pharmacological actions of FGF15/19 and FGF21 make them attractive drug candidates for treating metabolic disease.

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MASTR directs MyoD-dependent satellite cell differentiation during skeletal muscle regeneration.

Publication Date: 2012 Jan 15 PMID: 22279050
Authors: Mokalled, M. H. - Johnson, A. N. - Creemers, E. E. - Olson, E. N.
Journal: Genes Dev

In response to skeletal muscle injury, satellite cells, which function as a myogenic stem cell population, become activated, expand through proliferation, and ultimately fuse with each other and with damaged myofibers to promote muscle regeneration. Here, we show that members of the Myocardin family of transcriptional coactivators, MASTR and MRTF-A, are up-regulated in satellite cells in response to skeletal muscle injury and muscular dystrophy. Global and satellite cell-specific deletion of MASTR in mice impairs skeletal muscle regeneration. This impairment is substantially greater when MRTF-A is also deleted and is due to aberrant differentiation and excessive proliferation of satellite cells. These abnormalities mimic those associated with genetic deletion of MyoD, a master regulator of myogenesis, which is down-regulated in the absence of MASTR and MRTF-A. Consistent with an essential role of MASTR in transcriptional regulation of MyoD expression, MASTR activates a muscle-specific postnatal MyoD enhancer through associations with MEF2 and members of the Myocardin family. Our results provide new insights into the genetic circuitry of muscle regeneration and identify MASTR as a central regulator of this process.

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IGF2BP1 promotes cell migration by regulating MK5 and PTEN signaling.

Publication Date: 2012 Jan 15 PMID: 22279049
Authors: Stohr, N. - Kohn, M. - Lederer, M. - Glass, M. - Reinke, C. - Singer, R. H. - Huttelmaier, S.
Journal: Genes Dev

In primary neurons, the oncofetal RNA-binding protein IGF2BP1 (IGF2 mRNA-binding protein 1) controls spatially restricted beta-actin (ACTB) mRNA translation and modulates growth cone guidance. In cultured tumor-derived cells, IGF2BP1 was shown to regulate the formation of lamellipodia and invadopodia. However, how and via which target mRNAs IGF2BP1 controls the motility of tumor-derived cells has remained elusive. In this study, we reveal that IGF2BP1 promotes the velocity and directionality of tumor-derived cell migration by determining the cytoplasmic fate of two novel target mRNAs: MAPK4 and PTEN. Inhibition of MAPK4 mRNA translation by IGF2BP1 antagonizes MK5 activation and prevents phosphorylation of HSP27, which sequesters actin monomers available for F-actin polymerization. Consequently, HSP27-ACTB association is reduced, mobilizing cellular G-actin for polymerization in order to promote the velocity of cell migration. At the same time, stabilization of the PTEN mRNA by IGF2BP1 enhances PTEN expression and antagonizes PIP(3)-directed signaling. This enforces the directionality of cell migration in a RAC1-dependent manner by preventing additional lamellipodia from forming and sustaining cell polarization intrinsically. IGF2BP1 thus promotes the velocity and persistence of tumor cell migration by controlling the expression of signaling proteins. This fine-tunes and connects intracellular signaling networks in order to enhance actin dynamics and cell polarization.

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R-loop-mediated genome instability in mRNA cleavage and polyadenylation mutants.

Publication Date: 2012 Jan 15 PMID: 22279048
Authors: Stirling, P. C. - Chan, Y. A. - Minaker, S. W. - Aristizabal, M. J. - Barrett, I. - Sipahimalani, P. - Kobor, M. S. - Hieter, P.
Journal: Genes Dev

Genome instability via RNA:DNA hybrid-mediated R loops has been observed in mutants involved in various aspects of transcription and RNA processing. The prevalence of this mechanism among essential chromosome instability (CIN) genes remains unclear. In a secondary screen for increased Rad52 foci in CIN mutants, representing approximately 25% of essential genes, we identified seven essential subunits of the mRNA cleavage and polyadenylation (mCP) machinery. Genome-wide analysis of fragile sites by chromatin immunoprecipitation (ChIP) and microarray (ChIP-chip) of phosphorylated H2A in these mutants supported a transcription-dependent mechanism of DNA damage characteristic of R loops. In parallel, we directly detected increased RNA:DNA hybrid formation in mCP mutants and demonstrated that CIN is suppressed by expression of the R-loop-degrading enzyme RNaseH. To investigate the conservation of CIN in mCP mutants, we focused on FIP1L1, the human ortholog of yeast FIP1, a conserved mCP component that is part of an oncogenic fusion in eosinophilic leukemia. We found that truncation fusions of yeast FIP1 analogous to those in cancer cause loss of function and that siRNA knockdown of FIP1L1 in human cells increases DNA damage and chromosome breakage. Our findings illuminate how mCP maintains genome integrity by suppressing R-loop formation and suggest that this function may be relevant to certain human cancers.

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SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication.

Publication Date: 2012 Jan 15 PMID: 22279047
Authors: Betous, R. - Mason, A. C. - Rambo, R. P. - Bansbach, C. E. - Badu-Nkansah, A. - Sirbu, B. M. - Eichman, B. F. - Cortez, D.
Journal: Genes Dev

SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like1) maintains genome integrity during DNA replication. Here we investigated its mechanism of action. We found that SMARCAL1 travels with elongating replication forks, and its absence leads to MUS81-dependent double-strand break formation. Binding to specific nucleic acid substrates activates SMARCAL1 activity in a reaction that requires its HARP2 (Hep-A-related protein 2) domain. Homology modeling indicates that the HARP domain is similar in structure to the DNA-binding domain of the PUR proteins. Limited proteolysis, small-angle X-ray scattering, and functional assays indicate that the core enzymatic unit consists of the HARP2 and ATPase domains that fold into a stable structure. Surprisingly, SMARCAL1 is capable of binding three-way and four-way Holliday junctions and model replication forks that lack a designed ssDNA region. Furthermore, SMARCAL1 remodels these DNA substrates by promoting branch migration and fork regression. SMARCAL1 mutations that cause Schimke immunoosseous dysplasia or that inactivate the HARP2 domain abrogate these activities. These results suggest that SMARCAL1 continuously surveys replication forks for damage. If damage is present, it remodels the fork to promote repair and restart. Failures in the process lead to activation of an alternative repair mechanism that depends on MUS81-catalyzed cleavage of the damaged fork.

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Rif1 is a global regulator of timing of replication origin firing in fission yeast.

Publication Date: 2012 Jan 15 PMID: 22279046
Authors: Hayano, M. - Kanoh, Y. - Matsumoto, S. - Renard-Guillet, C. - Shirahige, K. - Masai, H.
Journal: Genes Dev

One of the long-standing questions in eukaryotic DNA replication is the mechanisms that determine where and when a particular segment of the genome is replicated. Cdc7/Hsk1 is a conserved kinase required for initiation of DNA replication and may affect the site selection and timing of origin firing. We identified rif1Delta, a null mutant of rif1(+), a conserved telomere-binding factor, as an efficient bypass mutant of fission yeast hsk1. Extensive deregulation of dormant origins over a wide range of the chromosomes occurs in rif1Delta in the presence or absence of hydroxyurea (HU). At the same time, many early-firing, efficient origins are suppressed or delayed in firing timing in rif1Delta. Rif1 binds not only to telomeres, but also to many specific locations on the arm segments that only partially overlap with the prereplicative complex assembly sites, although Rif1 tends to bind in the vicinity of the late/dormant origins activated in rif1Delta. The binding to the arm segments occurs through M to G1 phase in a manner independent of Taz1 and appears to be essential for the replication timing program during the normal cell cycle. Our data demonstrate that Rif1 is a critical determinant of the origin activation program on the fission yeast chromosomes.

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Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia.

Publication Date: 2012 Jan 15 PMID: 22279045
Authors: Glaser, S. P. - Lee, E. F. - Trounson, E. - Bouillet, P. - Wei, A. - Fairlie, W. D. - Izon, D. J. - Zuber, J. - Rappaport, A. R. - Herold, M. J. - Alexander, W. S. - Lowe, S. W. - Robb, L. - Strasser, A.
Journal: Genes Dev

Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-x(L) and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-x(L), Bcl-2, or Bcl-w, caused the death of transformed AML and could cure disease in AML-afflicted mice. Enforced expression of selective inhibitors of prosurvival Bcl-2 family members revealed that Mcl-1 is critical for survival of human AML cells. Thus, targeting of Mcl-1 or regulators of its expression may be a useful strategy for the treatment of AML.

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A zipcode unzipped.

Publication Date: 2012 Jan 15 PMID: 22279044
Authors: Doyle, M. - Kiebler, M. A.
Journal: Genes Dev

RNA-binding proteins (RBPs) exert many roles in the post-transcriptional regulation of gene expression in eukaryotic cells. However, our understanding of how they recognize their target RNAs in vivo remains limited. In the January 1, 2012, issue of Genes & Development, Patel and colleagues (p. 43-53) provide detailed mechanistic insights into how one of the best-studied RBPs, zipcode-binding protein 1 (ZBP1), recognizes a bipartite RNA sequence element within the beta-actin mRNA.

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Wnt signaling: the beta-cat(enin)'s meow.

Publication Date: 2012 Jan 15 PMID: 22279043
Authors: Bauer, M. - Willert, K.
Journal: Genes Dev

In a study in the December 15, 2011, issue of Genes & Development, Valenta and colleagues (pp. 2631-2643) constructed a series of beta-catenin mutants that allowed them to separate beta-catenin's activity as a mediator of Wnt signaling from its activity as cell adhesion component. In doing so, they uncovered some surprising properties of Wnt signaling.

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Recognition of the iso-ADP-ribose moiety in poly(ADP-ribose) by WWE domains suggests a general mechanism for poly(ADP-ribosyl)ation-dependent ubiquitination.

Publication Date: 2012 Feb 1 PMID: 22267412
Authors: Wang, Z. - Michaud, G. A. - Cheng, Z. - Zhang, Y. - Hinds, T. R. - Fan, E. - Cong, F. - Xu, W.
Journal: Genes Dev

Protein poly(ADP-ribosyl)ation and ubiquitination are two key post-translational modifications regulating many biological processes. Through crystallographic and biochemical analysis, we show that the RNF146 WWE domain recognizes poly(ADP-ribose) (PAR) by interacting with iso-ADP-ribose (iso-ADPR), the smallest internal PAR structural unit containing the characteristic ribose-ribose glycosidic bond formed during poly(ADP-ribosyl)ation. The key iso-ADPR-binding residues we identified are highly conserved among WWE domains. Binding assays further demonstrate that PAR binding is a common function for the WWE domain family. Since many WWE domain-containing proteins are known E3 ubiquitin ligases, our results suggest that protein poly(ADP-ribosyl)ation may be a general mechanism to target proteins for ubiquitination.

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Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization.

Publication Date: 2012 Jan 15 PMID: 22241783
Authors: Donlin, L. T. - Andresen, C. - Just, S. - Rudensky, E. - Pappas, C. T. - Kruger, M. - Jacobs, E. Y. - Unger, A. - Zieseniss, A. - Dobenecker, M. W. - Voelkel, T. - Chait, B. T. - Gregorio, C. C. - Rottbauer, W. - Tarakhovsky, A. - Linke, W. A.
Journal: Genes Dev

Protein lysine methylation is one of the most widespread post-translational modifications in the nuclei of eukaryotic cells. Methylated lysines on histones and nonhistone proteins promote the formation of protein complexes that control gene expression and DNA replication and repair. In the cytoplasm, however, the role of lysine methylation in protein complex formation is not well established. Here we report that the cytoplasmic protein chaperone Hsp90 is methylated by the lysine methyltransferase Smyd2 in various cell types. In muscle, Hsp90 methylation contributes to the formation of a protein complex containing Smyd2, Hsp90, and the sarcomeric protein titin. Deficiency in Smyd2 results in the loss of Hsp90 methylation, impaired titin stability, and altered muscle function. Collectively, our data reveal a cytoplasmic protein network that employs lysine methylation for the maintenance and function of skeletal muscle.

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Direct interaction of ligand-receptor pairs specifying stomatal patterning.

Publication Date: 2012 Jan 15 PMID: 22241782
Authors: Lee, J. S. - Kuroha, T. - Hnilova, M. - Khatayevich, D. - Kanaoka, M. M. - McAbee, J. M. - Sarikaya, M. - Tamerler, C. - Torii, K. U.
Journal: Genes Dev

Valves on the plant epidermis called stomata develop according to positional cues, which likely involve putative ligands (EPIDERMAL PATTERNING FACTORS [EPFs]) and putative receptors (ERECTA family receptor kinases and TOO MANY MOUTHS [TMM]) in Arabidopsis. Here we report the direct, robust, and saturable binding of bioactive EPF peptides to the ERECTA family. In contrast, TMM exhibits negligible binding to EPF1 but binding to EPF2. The ERECTA family forms receptor homomers in vivo. On the other hand, TMM associates with the ERECTA family but not with itself. While ERECTA family receptor kinases exhibit complex redundancy, blocking ERECTA and ERECTA-LIKE1 (ERL1) signaling confers specific insensitivity to EPF2 and EPF1, respectively. Our results place the ERECTA family as the primary receptors for EPFs with TMM as a signal modulator and establish EPF2-ERECTA and EPF1-ERL1 as ligand-receptor pairs specifying two steps of stomatal development: initiation and spacing divisions.

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