Hormones, second messengers and the reversible phosphorylation of proteins: An overview

Cohen, Philip

doi:10.1002/bies.950020206

Cited by 20 publications

(14 citation statements)

References 30 publications

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“…This finding agrees with results from an in vivo rat study that shows that glycogenolysis in skeletal muscle is more sensitive to insulin than is glucose transport and phosphorylation [1]. Interestingly, if AICAR does activate phosphorylase kinase our results suggests that phosphorylase kinase does not phosphorylate to inactivate glycogen synthase (Fig, 1), as has been previously suggested [27].…”

Section: Me Young Et Alifebssupporting

confidence: 93%

Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICAR — an activator of AMP‐activated protein kinase

1996

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We determined whether the cell permeable molecule AICAR, whose metabolite activates AMP-activated protein kinase (AMPK) in cells, affected glycogen metabolism in rat soleus muscle preparations in vitro. The basal and insulinstimulated rates of radioehemical lactate formation, net lactate release and glycogen synthesis were determined. AICAR stimulated net lactate release (but not radluchemical lactate formation) only at a basal concentration of insulin. An incteascd rate of glyeegenolysis was the likely cause of increased net lactate release as glycogen phosphorylase activity was signiflcandy increased by AICAR. AICAR-stimulated net lactate release and phosphorylase activity were potently inhibited by insulin.

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Section: Me Young Et Alifebssupporting

confidence: 93%

Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICAR — an activator of AMP‐activated protein kinase

1996

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“…Many of the physiological substrates for cyclic AMP-dependent protein kinase contain two adjacent basic residues N-terminal to the phosphorylation site, and the importance of this structural feature as a specificity determinant has been established (reviewed by Cohen, 1985). Site 1 of CAD also has this feature since the presence of a lysine or arginine preceding the N-terminal arginine can be inferred from the fact that this is a tryptic peptide.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation and activation of hamster carbamyl phosphate synthetase II by cAMP-dependent protein kinase. A novel mechanism for regulation of pyrimidine nucleotide biosynthesis.

Carrey¹,

Dg²,

Dg³

1985

The EMBO Journal

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The trifunctional protein CAD, which contains the first three enzyme activities of pyrimidine nucleotide biosynthesis (carbamyl phosphate synthetase II, aspartate transcarbamylase and dihydro-orotase), is phosphorylated stoichiometricaily by cyclic AMP-dependent protein kinase. Phosphorylation activates the ammonia-dependent carbamyl phosphate synthetase activity of the complex by reducing the apparent Km for ATP. This effect is particularly marked in the presence of the allosteric feedback inhibitor, UTP, when the apparent Km is reduced by >4-fold. Inhibition by physiological concentrations of UTP is substantially relieved by phosphorylation. Cyclic AMP-dependent protein kinase phosphorylates two serine residues on the protein termed sites 1 and 2, and the primary structures of tryptic peptides containing these sites have been determined: Site 1: Arg-Leu-Ser(P)-Ser-Phe-Val-Thr-Lys Site 2: lle-His-Arg-Ala-Ser(P)-Asp-Pro-Gly-Leu-Pro-Ala-Glu-Glu-Pro-Lys During the phosphorylation reaction, activation of the carbamyl phosphate synthetase shows a better correlation with occupancy of site 1 rather than site 2. Both phosphorylation and activation can be reversed using purified preparations of the catalytic subunits of protein phosphatases 1-and -2A, and inactivation also correlates better with dephosphorylation of site 1 rather than site 2. We believe this to be the first report that a key enzyme in nucleotide biosynthesis is regulated in a significant manner by reversible covalent modification. The physiological role of this phosphorylation in the stimulation of cell proliferation by growth factors and other mitogens is discussed.

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“…Biochemical responses are often elicited by the action of calmodulinor protein kinase C-dependent kinases and phosphorylases. These enzymes include cyclic nucleotide phosphodiesterase, phosphorylase kinase, adenylate cyclase, multiprotein kinase, calmodulin-dependent kinase, Ca2+-ATPase, and many others (134,140,141). Because these processes are somewhat distal from the [Ca2+]i signal, it is often difficult to experimentally establish the lead-dependent perturbation of the Ca2+ response system with suitable scientific rigor.…”

Section: Ca2+ Response Systemsmentioning

confidence: 99%

Cellular and molecular toxicity of lead in bone.

Pounds

Long

Rosen

1991

Environ Health Perspect

292

131

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To fully understand the significance of bone as a target tissue of lead toxicity, as well as a reservoir of systemic lead, it is necessary to define the effects of lead on the cellular components of bone. Skeletal development and the regulation of skeletal mass are ultimately determined by the four different types of cells: osteoblasts, lining cells, osteoclasts, and osteocytes. These cells, which line and penetrate the mineralized matrix, are responsible for matrix formation, mineralization, and bone resorption, under the control of both systemic and local factors. Systemic components of regulation include parathyroid hormone, 1,25-dihydroxyvitamin D3, and calcitonin: local regulators include numerous cytokines and growth factors. Lead intoxication directly and indirectly alters many aspects of bone cell function. First, lead may indirectly alter bone cell function through changes in the circulating levels of those hormones, particularly 1,25-dihydroxyvitamin D3, which modulate bone cell function. These hormonal changes have been well established in clinical studies, although the functional significance remains to be established. Second, lead may directly alter bone cell function by perturbing the ability of bone cells to respond to hormonal regulation. For example, the 1,25-dihydroxyvitamin D3-stimulated synthesis of osteocalcin, a calcium-binding protein synthesized by osteoblastic bone cells, is inhibited by low levels of lead. Impaired osteocalcin production may inhibit new bone formation, as well as the functional coupling of osteoblasts and osteoclasts. Third, lead may impair the ability of cells to synthesize or secrete other components of the bone matrix, such as collagen or bone sialoproteins (osteopontin). Finally, lead may directly effect or substitute for calcium in the active sites of the calcium messenger system, resulting in loss of physiological regulation. The effects of lead on the recruitment and differentiation of bone cells remains to be established. Compartmental analysis indicates that the kinetic distribution and behavior of intracellular lead in osteoblasts and osteoclasts is similar to several other cell types. Many of the toxic effects of lead on bone cell function may be produced by perturbation of the calcium and cAMP messenger systems in these cells.

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Hormones, second messengers and the reversible phosphorylation of proteins: An overview

Cited by 20 publications

References 30 publications

Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICAR — an activator of AMP‐activated protein kinase

Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICAR — an activator of AMP‐activated protein kinase

Phosphorylation and activation of hamster carbamyl phosphate synthetase II by cAMP-dependent protein kinase. A novel mechanism for regulation of pyrimidine nucleotide biosynthesis.

Cellular and molecular toxicity of lead in bone.

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