The Regulation of Amino Acid and Protein Metabolism by Growth Hormone

Fryburg, David A.; Barrett, Eugene J.

doi:10.1002/cphy.cp070517

Cited by 2 publications

(3 citation statements)

References 261 publications

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“…In the category "focal adhesion," the phosphosites in filamin, zyxin, parvin, and Ppp1r12a were not previously known to be GH regulated. The identification of proteins in the categories "insulin signaling pathway" and "mTOR signaling pathway" that exhibit increased levels of phosphorylation in GH-treated cells are consistent with the known role of GH in the regulation of metabolism and cell growth (1,2). Erk1, Erk2, and TSC2 were known previously to be phosphorylated in response to GH on the sites we identified.…”

Section: Functional Analysis Of Phosphoproteins Identified After 5 Ansupporting

confidence: 84%

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Research Resource: Identification of Novel Growth Hormone-Regulated Phosphorylation Sites by Quantitative Phosphoproteomics

Ray

Kweon

Argetsinger

et al. 2012

Molecular Endocrinology

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GH and GH receptors are expressed throughout life, and GH elicits a diverse range of responses, including growth and altered metabolism. It is therefore important to understand the full spectrum of GH signaling pathways and cellular responses. We applied mass spectrometry-based phosphoproteomics combined with stable isotope labeling with amino acids in cell culture to identify proteins rapidly phosphorylated in response to GH in 3T3-F442A preadipocytes. We identified 132 phosphosites in 95 proteins that exhibited rapid (5 or 15 min) GH-dependent statistically significant increases in phosphorylation by more than or equal to 50% and 96 phosphosites in 46 proteins that were down-regulated by GH by more than or equal to 30%. Several of the GH-stimulated phosphorylation sites were known (e.g. regulatory Thr/Tyr in Erks 1 and 2, Tyr in signal transducers and activators of transcription (Stat) 5a and 5b, Ser939 in tuberous sclerosis protein (TSC) 2 or tuberin). The remaining 126 GH-stimulated sites were not previously associated with GH. Kyoto Encyclopedia of Genes and Genomes pathway analysis of GH-stimulated sites indicated enrichment in proteins associated with the insulin and mammalian target of rapamycin (mTOR) pathways, regulation of the actin cytoskeleton, and focal adhesions. Akt/protein kinase A consensus sites (RXRXXS/T) were the most commonly phosphorylated consensus sites. Immunoblotting confirmed GH-stimulated phosphorylation of all seven novel GH-dependent sites tested [regulatory sites in proline-rich Akt substrate, 40 kDA (PRAS40), regulatory associated protein of mTOR, ATP-citrate lyase, Na+/H+ exchanger-1, N-myc downstream regulated gene 1, and Shc]). The immunoblot results suggest that many, if not most, of the GH-stimulated phosphosites identified in this large-scale quantitative phosphoproteomics analysis, including sites in multiple proteins in the Akt/ mTOR complex 1 pathway, are phosphorylated in response to GH. Their identification significantly broadens our thinking of GH-regulated cell functions.

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Section: Functional Analysis Of Phosphoproteins Identified After 5 Ansupporting

confidence: 84%

“…GH, which binds to the ubiquitously expressed GH receptor, is an important regulator of body growth, development, and metabolism ( 1 , 2 ). Patients with abnormally high levels of circulating GH throughout life (acromegaly) are extremely tall and may have enlarged liver, heart, kidneys, and/or other organs.…”

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confidence: 99%

Research Resource: Identification of Novel Growth Hormone-Regulated Phosphorylation Sites by Quantitative Phosphoproteomics

Ray

Kweon

Argetsinger

et al. 2012

Molecular Endocrinology

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“…Among its diverse actions, GH promotes statural growth in conjunction with Insulin-like Growth Factor 1 (IGF-1) by stimulating chondrocytes in long bones (4)(5)(6)(7). GH promotes a relative increase in lean body mass and decrease in body lipid, reflecting changes that include the ability of GH to increase cellular protein synthesis, stimulate lipolysis and impair lipogenesis under physiological conditions (8,9). GH excess can result in acromegaly and insulin resistance (8,10,11).…”

Section: Introductionmentioning

confidence: 99%

Multiple mechanisms of growth hormone-regulated gene transcription

Ceseña

Cui

Piwien-Pilipuk³

et al. 2007

Molecular Genetics and Metabolism

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Diverse physiological actions of growth hormone (GH) are mediated by changes in gene transcription. Transcription can be regulated at several levels, including post-translational modification of transcription factors, and formation of multiprotein complexes involving transcription factors, co-regulators and additional nuclear proteins; these serve as targets for regulation by hormones and signaling pathways. Evidence that GH regulates transcription at multiple levels is exemplified by analysis of the proto-oncogene c-fos. Among the GH-regulated transcription factors on c-fos, C/EBPβ appears to be key, since depletion of C/EBPβ by RNA interference blocks the stimulation of c-fos by GH. The phosphorylation state of C/EBPβ and its ability to activate transcription are regulated by GH through MAPK and PI3K/Akt-mediated signaling cascades. The acetylation of C/EBPβ also contributes to its ability to activate c-fos transcription. These and other post-translational modifications of C/EBPβ appear to be integrated for regulation of transcription by GH. The formation of nuclear proteins into complexes associated with DNA-bound transcription factors is also regulated by GH. Both C/EBPβ and the co-activator p300 are recruited to c-fos in response to GH, altering c-fos promoter activation. In addition, GH rapidly induces spatio-temporal relocalization of C/EBPβ within the nucleus. Thus, GH-regulated gene transcription mediated by C/ EBPβ reflects the integration of diverse mechanisms including post-translational modifications, modulation of protein complexes associated with DNA and relocalization of gene regulatory proteins. Similar integration involving other transcription factors, including Stats, appears to be a feature of regulation by GH of other gene targets.

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The Regulation of Amino Acid and Protein Metabolism by Growth Hormone

Cited by 2 publications

References 261 publications

Research Resource: Identification of Novel Growth Hormone-Regulated Phosphorylation Sites by Quantitative Phosphoproteomics

Research Resource: Identification of Novel Growth Hormone-Regulated Phosphorylation Sites by Quantitative Phosphoproteomics

Multiple mechanisms of growth hormone-regulated gene transcription

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