Mitogenesis and protein synthesis: A role for ribosomal protein S6 phosphorylation?

Stewart, Michael; Thomas, George

doi:10.1002/bies.950161107

Cited by 76 publications

(53 citation statements)

References 56 publications

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“…Another mechanism by which AII might stimulate translation is by phosphorylating the 40 S ribosomal protein S6 through the activation of p70 S6K (4). S6 phosphorylation has been closely correlated with the stimulatory effect of growth factors on translation (42,43). Our observation that rapamycin treatment of aortic SMC inhibits up to 60 -80% of AII-stimulated protein synthesis would be consistent with this notion.…”

Section: Discussionsupporting

confidence: 79%

Angiotensin II Stimulates Phosphorylation of the Translational Repressor 4E-binding Protein 1 by a Mitogen-activated Protein Kinase-independent Mechanism

Fleurent

Gingras

Sonenberg

et al. 1997

Journal of Biological Chemistry

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The peptide hormone angiotensin II (AII) 1 potently stimulates protein synthesis and induces cellular hypertrophy in cultured rat vascular SMC (1-4). This growth-promoting effect is mediated by the AT 1 receptor subtype, a member of the G protein-coupled receptors superfamily (4, 5). However, the molecular basis for the hypertrophic action of the hormone remains largely unknown. In vascular SMC, the augmented rate of protein synthesis induced by AII is associated with a widespread but selective increase in the content of highly abundant extracellular matrix (6 -8) and contractile proteins (9). The increased synthesis of proteins like ␣-actin, collagen, or thrombospondin is accompanied by a corresponding increase in their specific mRNAs, which is indicative of the importance of transcriptional control in the overall stimulation of protein synthesis (6 -9). In agreement with this notion, the transcriptional inhibitor actinomycin D can prevent AII-induced accumulation of proteins in chronically stimulated vascular SMC (2). 2 On the other hand, the global nature of the trophic effect of AII suggests that regulatory changes at the translational level are likely to be involved in the hormone response.The major locus of regulation in protein synthesis is generally at the initiation step of mRNA translation (for review, see Refs. 10 -12). This step is controlled by the concerted action of a number of initiation factors which are extensively regulated by phosphorylation/dephosphorylation mechanisms (13, 14). The rate-limiting step in translation initiation is the binding of mRNA to the small 40 S ribosomal subunit, which requires the participation of initiation factor eIF4F (15). eIF4F exists as a protein complex composed of three polypeptides: eIF4E (the cap-binding protein), eIF4G, and eIF4A, a RNA helicase. The interaction of eIF4F with the mRNA, followed by the unwinding of the mRNA 5Ј secondary structure facilitates the attachment of the 40 S ribosomal subunit which moves along the mRNA scanning for the initiator AUG codon (10 -12, 15). eIF4E is the least abundant among all initiation factors and thus a critical regulatory component of the protein synthetic machinery (16,17). Overexpression of eIF4E leads to deregulation of cell growth (18) and oncogenic transformation (19), whereas its depletion decreases protein synthesis (20). The activity of eIF4E is regulated by 4E-BP1 (also known as PHAS-I) and 4E-BP2, two recently identified proteins which specifically bind to eIF4E and inhibit cap-dependent translation (21, 22). Phosphorylation of 4E-BP1 in response to insulin causes its dissociation from eIF4E, thereby relieving translational inhibition (21,22). 4E-BP1 is phosphorylated by ERK2 on a single serine residue in vitro (23), and this phosphorylation markedly decreases the affinity of the protein for eIF4E (22). In cultured adipocytes, the epidermal growth factor-stimulated 4E-BP1 kinase activity elutes in two peaks that correspond to the peaks of ERK isoforms after anion exchange chromatography (29). Based on the...

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Section: Discussionsupporting

confidence: 79%

Angiotensin II Stimulates Phosphorylation of the Translational Repressor 4E-binding Protein 1 by a Mitogen-activated Protein Kinase-independent Mechanism

Fleurent

Gingras

Sonenberg

et al. 1997

Journal of Biological Chemistry

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“…An exciting, recent, observation is that the selective enhancement of translation of several of these mRNAs in growth-stimulated cells is impaired by the immunosuppressive drug, rapamycin [272,2731. This drug blocks the signalling pathway involving the p70S", which is responsible for the phosphorylation of ribosomal protein S6 in response to a variety of hormones and growth factors [274]. Thus the translation of mRNAs bearing 5'-oligopyrimidine tracts may be regulated by this pathway, perhaps by a phosphorylatioddephosphorylation mechanism involving a specific binding protein.…”

Section: Structural Features In the Untranslated Regions Of Mrnas Thamentioning

confidence: 99%

Initiation of Protein Synthesis in Eukaryotic Cells

Pain

1996

European Journal of Biochemistry

674

471

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It is becoming increasingly apparent that translational control plays an important role in the regulation of gene expression in eukaryotic cells. Most of the known physiological effects on translation are exerted at the level of polypeptide chain initiation. Research on initiation of translation over the past five years has yielded much new information, which can be divided into three main areas: (a) structure and function of initiation factors (including identification by sequencing studies of consensus domains and motifs) and investigation of protein-protein and protein-RNA interactions during initiation ; (b) physiological regulation of initiation factor activities and (c) identification of features in the 5' and 3' untranslated regions of messenger RNA molecules that regulate the selection of these mRNAs for translation. This review aims to assess recent progress in these three areas and to explore their interrelationships.Keywords: translation; initiation; mRNA ; review, regulation.In 1986 I published a review describing the mechanism and regulation of initiation of translation in mammalian cells 121. By that time most of the polypeptide initiation factors catalysing this process had been extensively purified and their individual activities studied in various in vitro systems. Several of them had been shown to be phosphoproteins and, in one case, eukaryotic initiation factor-2 (eIF-2), the effects of phosphorylation had been elucidated and two physiological kinases had been identified. There seemed to be a feeling in some circles that the most interesting problems in protein synthesis had been solved, and that only a few rather boring nuts and bolts awaited discovery.Over the intervening ten years there has been an explosion of research activity in this area, largely fuelled by information yielded by molecular biology and genetic techniques. Cloning of cDNAs encoding initiation factors has revealed domain structures indicative of function and potential regulatory mechanisms. Experiments exploiting the ability to elucidate and manipulate mRNA sequences have demonstrated that translational control contributes to changes in patterns of gene expression during growth, differentiation and development to an extent that would have seemed inconceivable in 1985. Such experiments have, in particular, revealed important roles for structural fea- UTR, untranslated region (in mRNA); RRM, RNA recognition motif; ORF, open reading frame; EMCV, encephalomyocarditis virus ; FMDV, foot-and-mouth disease virus ; IRES, internal ribosome entry segment ; PTB, polypyrimidine tract binding protein ; HCR, heme-controlled repressor; PKR, protein kinase activated by RNA; dsRNA, doublestranded RNA; p70ShK and p 9 0 k , 70 kDa and 90-92 kDa ribosomal protein S6 kinases ; GSK, glycogen synthase kinase ; IRE, iron-regulatory element; IRP, iron regulatory protein ; PABP, poly(A) binding protein; AMV, alfalfa mosaic virus ; CPE, cytoplasmic polyadenylation element (also known as ACE, adenylation control element); MAP, mitogenactivated protei...

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“…In higher eukaryotes, the 40S ribosomal subunit is made up of an 18S RNA and a total of 33 proteins, many of which are phosphorylated 1; 2 . However, of these phosphorylated proteins, ribosomal protein S6 (rpS6) has received the most attention as its phosphorylation is rapidly induced in response to nutritional, hormonal and mitogenic stimuli and it was the first identified substrate for p70S6K (S6K1) 3 .…”

Section: Introductionmentioning

confidence: 99%

Identification of cAMP-Dependent Kinase as a Third in Vivo Ribosomal Protein S6 Kinase in Pancreatic β-Cells

Moore

Xie

Gomez

et al. 2009

Journal of Molecular Biology

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Ribosomal protein S6 (rpS6) is phosphorylated in vivo by isoforms of p70 S6 kinase (S6K) and p90 ribosomal S6 kinase (Rsk) and there is good evidence that it plays a positive role in controlling pancreatic β-cell size and function. In this report, we demonstrate, in the pancreatic β-cell line MIN6 and islets of Langerhans, that agents which stimulate increases in cAMP, such as glucagon like peptide-1 (GLP1) or forskolin, lead to the phosphorylation of rpS6 exclusively at Ser(235/236) independently of the activation of the currently known in vivo rpS6 kinases via a pathway that is sensitive to inhibitors of cAMP-dependent kinase (PKA). This cAMP-dependent rpS6 kinase activity is also sensitive to PKI in vitro and PKA exclusively phosphorylates recombinant rpS6 on Ser(235/236) in vitro. Taken together, we conclude that PKA can phosphorylate rpS6 exclusively at Ser(235/236) in vivo in pancreatic β-cells, thus providing a potentially important link between cAMP signalling and the regulation of protein synthesis. Lastly, we provide evidence that PKA is also likely to phosphorylate rpS6 on Ser(235/236) in vivo in a number of other mammalian cell types. IntroductionThe Eukaryotic 80S ribosome is a macromolecular complex composed of a small 40S subunit, which decodes the mRNA, and a large 60S subunit, which is involved in peptidyl transfer. In higher eukaryotes, the 40S ribosomal subunit is made up of an 18S RNA and a total of 33 proteins, many of which are phosphorylated 1; 2 . However, of these phosphorylated proteins, ribosomal protein S6 (rpS6) has received the most attention as its phosphorylation is rapidly induced in response to nutritional, hormonal and mitogenic stimuli and it was the first identified substrate for p70S6K (S6K1) 3 . rpS6 is phosphorylated by S6K at the C-terminus on Ser236, Ser235, Ser240, Ser244 and Ser247 in vitro 4 , which correspond to sites phosphorylated in vivo 5 . Deletion of the S6K (dS6K) gene in Drosophilia is embryonic lethal; however, a few flies survive and these have reduced body mass as a result of a smaller cell size rather than cell number 6 . Mammalian cells express two isoforms of S6K, S6K1 and S6K2, each encoded by a separate gene 7 and in mice, deletion of the S6K1 gene (S6K1 -/-) is not lethal but the mice are significantly smaller than their wild type counterparts due to decreased cell size rather than decreased cell number 7 8 . In contrast, mice in which the S6K2 gene is deleted (S6K2 -/-) show a normal body and cell size compared to wild type littermates 9 . Mice in which both S6K1 and S6K2 (S6K1 -/-/2 -/-) were deleted have a similar phenotype to that of S6K1 -/-mice but show a significant decrease in viability compared to the S6K1 -/-mice 9 . Importantly, especially in relation to 2 this study, the phosphorylation of rpS6 appears to play a particularly significant role in controlling pancreatic β-cell size and function as S6K1 -/-mice and knock-in mouse in which all five phosphorylatable serine residues within rpS6 are substituted to alanines (rpS6 P-/-) have compar...

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Mitogenesis and protein synthesis: A role for ribosomal protein S6 phosphorylation?

Cited by 76 publications

References 56 publications

Angiotensin II Stimulates Phosphorylation of the Translational Repressor 4E-binding Protein 1 by a Mitogen-activated Protein Kinase-independent Mechanism

Angiotensin II Stimulates Phosphorylation of the Translational Repressor 4E-binding Protein 1 by a Mitogen-activated Protein Kinase-independent Mechanism

Initiation of Protein Synthesis in Eukaryotic Cells

Identification of cAMP-Dependent Kinase as a Third in Vivo Ribosomal Protein S6 Kinase in Pancreatic β-Cells

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