scholarly journals Class III PI-3-kinase activates phospholipase D in an amino acid–sensing mTORC1 pathway

2011 ◽  
Vol 195 (3) ◽  
pp. 435-447 ◽  
Author(s):  
Mee-Sup Yoon ◽  
Guangwei Du ◽  
Jonathan M. Backer ◽  
Michael A. Frohman ◽  
Jie Chen
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Phospholipase D ◽  
Acid Activation ◽  
Class Iii ◽  
Amino Acid Activation ◽  
Px Domain ◽  
Amino Acid Sensing ◽  
Mtorc1 Activation ◽  
Phosphatidylinositol 3

The rapamycin-sensitive mammalian target of rapamycin (mTOR) complex, mTORC1, regulates cell growth in response to mitogenic signals and amino acid availability. Phospholipase D (PLD) and its product, phosphatidic acid, have been established as mediators of mitogenic activation of mTORC1. In this study, we identify a novel role for PLD1 in an amino acid–sensing pathway. We find that amino acids activate PLD1 and that PLD1 is indispensable for amino acid activation of mTORC1. Activation of PLD1 by amino acids requires the class III phosphatidylinositol 3-kinase hVps34, which stimulates PLD1 activity through a functional interaction between phosphatidylinositol 3-phosphate and the Phox homology (PX) domain of PLD1. Furthermore, amino acids stimulate PLD1 translocation to the lysosomal region where mTORC1 activation occurs in an hVps34-dependent manner, and this translocation is necessary for mTORC1 activation. The PX domain is required for PLD1 translocation, mTORC1 activation, and cell size regulation. Finally, we show that the hVps34-PLD1 pathway acts independently of, and in parallel to, the Rag pathway in regulating amino acid activation of mTORC1.

scholarly journals Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis

2013 ◽  
Vol 24 (23) ◽  
pp. 3754-3763 ◽  
Author(s):  
Mee-Sup Yoon ◽  
Jie Chen
Keyword(s):  
Amino Acid ◽  
Growth Regulation ◽  
Myogenic Differentiation ◽  
Mammalian Target Of Rapamycin ◽  
Acid Activation ◽  
Class Iii ◽  
Independent Manner ◽  
Inhibitory Function ◽  
Amino Acid Availability ◽  
Amino Acid Sensing

Signaling through the mammalian target of rapamycin (mTOR) in response to amino acid availability controls many cellular and developmental processes. mTOR is a master regulator of myogenic differentiation, but the pathways mediating amino acid signals in this process are not known. Here we examine the Rag GTPases and the class III phosphoinositide 3-kinase (PI3K) Vps34, two mediators of amino acid signals upstream of mTOR complex 1 (mTORC1) in cell growth regulation, for their potential involvement in myogenesis. We find that, although both Rag and Vps34 mediate amino acid activation of mTORC1 in C2C12 myoblasts, they have opposing functions in myogenic differentiation. Knockdown of RagA/B enhances, whereas overexpression of active RagB/C mutants impairs, differentiation, and this inhibitory function of Rag is mediated by mTORC1 suppression of the IRS1-PI3K-Akt pathway. On the other hand, Vps34 is required for myogenic differentiation. Amino acids activate a Vps34-phospholipase D1 (PLD1) pathway that controls the production of insulin-like growth factor II, an autocrine inducer of differentiation, through the Igf2 muscle enhancer. The product of PLD, phosphatidic acid, activates the enhancer in a rapamycin-sensitive but mTOR kinase–independent manner. Our results uncover amino acid–sensing mechanisms controlling the homeostasis of myogenesis and underline the versatility and context dependence of mTOR signaling.

Discussion: Amino-acid activation by individual enzymes

1958 ◽  
Vol 149 (936) ◽  
pp. 401-402
Keyword(s):  
Amino Acids ◽  
Molecular Weight ◽  
Amino Acid ◽  
Distribution Pattern ◽  
Mammary Tissue ◽  
Low Molecular Weight ◽  
Major Protein ◽  
Acid Activation ◽  
Amino Acid Activation ◽  
Interesting Paper

I should like to comment on one aspect of Dr Gutfreund’s interesting paper. As he mentioned, we have found evidence that amino acids, after becoming enzymically activated by ATP through the formation of an enzyme-bound amino acyladenylate compound, are transferred to a low molecular weight RNA which, by accident or design, resides in the same crude activating enzyme fraction. It is gratifying that Dr Gutfreund has found a distribution pattern of amino acids on this RNA which roughly agrees with the pattern in the major protein products of mammary tissue. He points out, however, that there is no such correlation when one looks at the pattern of amino-acid activation. Indeed, because of this anomaly, some workers have devised theories of activation involving transacylation steps to account for activation of those amino acids for which an enzyme has not been found. Dr Gutfreund implies that there is much confusion and mystery here, and even suggests that the specificity of activation might be accounted for by soluble RNA , rather than by individual enzymes.

NON-RIBOSOMAL POLYPEPTIDE SYNTHESIS

1973 ◽  
Vol 74 (Suppl) ◽  
pp. S294-S300 ◽  
Author(s):  
Fritz Lipmann
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Acid Activation ◽  
Bacillus Brevis ◽  
Amino Acid Activation ◽  
Molecular Weights ◽  
Polypeptide Synthesis ◽  
Secondary Transfer ◽  
Sequential Addition ◽  
Made In

ABSTRACT The biosynthesis of the cyclic decapeptide antibiotic, tyrocidine, was analyzed in particle-free supernatant fractions of RNase-treated homogenates of Bacillus brevis ATCC 8185. From the extracts, three complementary fractions with molecular weights of (1) 100 000, (2) 230 000, and (3) 440 000 were obtained. (1) activates and racemizes the initiating phenylalanine, (2) activates the three following amino acids, and (3) activates the last six amino acids by primary reaction with ATP to AMP-amino acid and secondary transfer to an enzyme-bound -SH. The enzymes alone fix amino acids but do not polymerize. The mixture, on sequential addition of amino acids + ATP, polymerizes first to enzyme-bound polypeptides, which after addition of all ten amino acids, cyclize. The enzymes (2) and (3) each contain one mole of 4'-phosphopantetheine which appears to act in transpeptidation. By mild autolysis and dodecyl sulphate gel electrophoresis, the polyenzymes may be split to subunits of 70 000 molecular weight, retaining only amino acid activation. In recent attempts to analyze the biosynthesis of the thyrotropic release hormone, a tripeptide made in the hypothalamus, we have met with great difficulties due to the presence of potent peptidases in brain preparations.

scholarly journals Streptogramin B biosynthesis in Streptomyces pristinaespiralis and Streptomyces virginiae: molecular characterization of the last structural peptide synthetase gene.

1997 ◽  
Vol 41 (9) ◽  
pp. 1904-1909 ◽  
Author(s):  
V de Crécy-Lagard ◽  
W Saurin ◽  
D Thibaut ◽  
P Gil ◽  
L Naudin ◽  
...  
Keyword(s):  
Amino Acid ◽  
Acid Activation ◽  
Activation Domains ◽  
Amino Acid Activation ◽  
Streptomyces Virginiae ◽  
Streptomyces Pristinaespiralis ◽  
Degenerate Oligonucleotide ◽  
Peptide Synthetase ◽  
Different Origins

Streptomyces pristinaespiralis and S. virginiae both produce closely related hexadepsipeptide antibiotics of the streptogramin B family. Pristinamycins I and virginiamycins S differ only in the fifth incorporated precursor, di(mono)methylated amine and phenylalanine, respectively. By using degenerate oligonucleotide probes derived from internal sequences of the purified S. pristinaespiralis SnbD and SnbE proteins, the genes from two streptogramin B producers, S. pristinaespiralis and S. virginiae, encoding the peptide synthetase involved in the activation and incorporation of the last four precursors (proline, 4-dimethylparaaminophenylalanine [for pristinamycin I(A)] or phenylalanine [for virginiamycin S], pipecolic acid, and phenylglycine) were cloned. Analysis of the sequence revealed that SnbD and SnbE are encoded by a unique snbDE gene. SnbDE (4,849 amino acids [aa]) contains four amino acid activation domains, four condensation domains, an N-methylation domain, and a C-terminal thioesterase domain. Comparison of the sequences of 55 amino acid-activating modules from different origins confirmed that these sequences contain enough information for the performance of legitimate predictions of their substrate specificity. Partial sequencing (1,993 aa) of the SnbDE protein of S. virginiae allowed comparison of the proline and aromatic acid activation domains of the two species and the identification of coupled frameshift mutations.

scholarly journals The Mechanism of Amino Acid Activation: the Work of Mahlon Hoagland

2009 ◽  
Vol 284 (25) ◽  
pp. e7-e8
Author(s):  
Nicole Kresge ◽  
Robert D. Simoni ◽  
Robert L. Hill
Keyword(s):  
Amino Acid ◽  
Acid Activation ◽  
Amino Acid Activation

scholarly journals Activation of the SPS Amino Acid-Sensing Pathway in Saccharomyces cerevisiae Correlates with the Phosphorylation State of a Sensor Component, Ptr3

2007 ◽  
Vol 28 (2) ◽  
pp. 551-563 ◽  
Author(s):  
Zhengchang Liu ◽  
Janet Thornton ◽  
Mário Spírek ◽  
Ronald A. Butow
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Amino Acids ◽  
Amino Acid ◽  
Nuclear Translocation ◽  
Proteolytic Processing ◽  
Casein Kinase I ◽  
Positive Regulators ◽  
Amino Acid Permeases ◽  
Amino Acid Sensing ◽  
Amino Acid Sensor

ABSTRACT Cells of the budding yeast Saccharomyces cerevisiae sense extracellular amino acids and activate expression of amino acid permeases through the SPS-sensing pathway, which consists of Ssy1, an amino acid sensor on the plasma membrane, and two downstream factors, Ptr3 and Ssy5. Upon activation of SPS signaling, two transcription factors, Stp1 and Stp2, undergo Ssy5-dependent proteolytic processing that enables their nuclear translocation. Here we show that Ptr3 is a phosphoprotein whose hyperphosphorylation is increased by external amino acids and is dependent on Ssy1 but not on Ssy5. A deletion mutation in GRR1, encoding a component of the SCFGrr1 E3 ubiquitin ligase, blocks amino acid-induced hyperphosphorylation of Ptr3. We found that two casein kinase I (CKI) proteins, Yck1 and Yck2, previously identified as positive regulators of SPS signaling, are required for hyperphosphorylation of Ptr3. Loss- and gain-of-function mutations in PTR3 result in decreased and increased Ptr3 hyperphosporylation, respectively. We found that a defect in PP2A phosphatase activity leads to the hyperphosphorylation of Ptr3 and constitutive activation of SPS signaling. Two-hybrid analysis revealed interactions between the N-terminal signal transduction domain of Ssy1 with Ptr3 and Yck1. Our findings reveal that CKI and PP2A phosphatase play antagonistic roles in SPS sensing by regulating Ptr3 phosphorylation.

Amino-Acid Activation in Tissues of Early Embryos

Nature ◽  
1961 ◽  
Vol 191 (4792) ◽  
pp. 1006-1007 ◽  
Author(s):  
ELIZABETH M. DEUCHAR
Keyword(s):  
Amino Acid ◽  
Acid Activation ◽  
Amino Acid Activation ◽  
Early Embryos

scholarly journals Use of a spectrophotometric assay to evaluate amino acid activation and tRNA charging

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Japheth Mobisa ◽  
Kyra Samuel ◽  
Idiuso Okeke ◽  
Jacquelyn Castaneda ◽  
Thanh Trinh ◽  
...  
Keyword(s):  
Amino Acid ◽  
Spectrophotometric Assay ◽  
Acid Activation ◽  
Amino Acid Activation
Sign in / Sign up

Export Citation Format

Share Document