Gs3k

Fig. 2.4.1 Signal chain for regulation of many metabolic processes by insulin. Insulin binds to its receptor in the cell membrane leading to auto-phosphorylation of tyrosine residues in the receptor protein. This leads to interaction with a family of proteins known as insulin receptor substrates (IRS), which themselves become phosphorylated and then interact with the enzyme phosphatidylinositol-3-kinase (PI3K on figure). PI3K generates phosphatidylinositol (3',4',5')-trisphosphate (PIP3 on figure; see Box 2.3, Fig. 2.3.2 for structure) in the inner surface of the membrane, which acts through the enzyme 3'-phosphoinositide dependent kinase-1 (PDK1) to phosphorylate (and activate) protein kinase B (PKB). Activated PKB leads to several cellular responses to insulin including inhibition of lipolysis (see Fig. 2.4.3), increased glucose transport (see Fig. 2.5), effects on DNA transcription, and also phosphorylation and inactivation of glycogen synthase kinase 3 (GSK3). Inactivation of GSK3 also leads to multiple cellular effects including stimulation of glycogen synthesis (discussed later; see Box 4.1) and, again, effects on gene expression and also effects on protein chain initiation (i.e. mRNA translation). Although it seems odd to speak of inactivation of an enzyme leading to downstream events, these are brought about by specific phosphatases that are then free to dephos-phorylate the proteins involved.

phosphatases may themselves be regulated, in some cases also by phosphorylation and dephosphorylation.

2.4 Longer-term control of enzyme activity

2.4.1 Hormones and longer-term control of enzyme activity

The events shown in Box 2.4 involve mainly reversible phosphorylation of enzymes, changing their activity rapidly. These are mechanisms for producing rapid changes in flux. But binding of hormones to cell-surface receptors can also regulate pathways over a longer time-scale by altering the expression of genes coding for enzymes of the pathway.

2.4.1.1 Insulin and control of gene expression

Insulin controls the expression of a large number of genes; some are suppressed, some are up-regulated (expression increased). Some of the genes whose expression is altered by insulin and which produce proteins involved in energy

Adrenaline p-adrenergii receptor

Glucagon

GTP'

ATP cAMP

Glucagon

GTP'

ATP cAMP

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