Tyrosine Kinase Second Messenger System

Insulin promotes glucose and amino acid transport and stimulates glycogen, fat, and protein synthesis in its target organs—primarily the liver, skeletal muscles, and adipose tissue. These effects are achieved by means of a mechanism of action that is quite complex, and in some ways still incompletely understood. Nevertheless, it is known that insulin's mechanism of action bears similarities to the mechanism of action of other regulatory molecules known as growth factors. These growth factors, examples of which are epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and insulin-like growth factors (IGFs) are autocrine regulators (described at the end of this chapter).

In the case of insulin and the growth factors, the receptor protein is located in the plasma membrane and is itself a kind of enzyme known as a tyrosine kinase. A kinase is an enzyme that adds phosphate groups to proteins, and a tyrosine kinase

Endocrine Glands 297

Endocrine Glands 297

Ip3 Activation Pdgfr

■ Figure 11.9 The phospholipase C-Ca2+ second-messenger system. Some hormones, when they bind to their membrane receptors, activate phospholipase C (PLC). This enzyme catalyzes the formation of inositol triphosphate (IP3), which causes Ca2+ channels to open in the endoplasmic reticulum. Ca2+ is thus released and acts as a second messenger in the action of the hormone.

Liver cell

Beta-adrenergic effect of epinephrine

Beta-adrenergic effect of epinephrine

Glycogen

Active protein kinase

Glycogen

Glucose 1-phosphate

Active protein kinase mU

Alpha-adrenergic effect of epinephrine

Ca2+

Alpha-adrenergic effect of epinephrine

Ca2+

Glucose 6-phosphate

Free glucose

Figure 11.10 Epinephrine can act through two second-messenger systems. The stimulation of P-adrenergic receptors invokes the cAMP second-messenger system, and the stimulation of the a-adrenergic receptors invokes the Ca2+ second-messenger system.

specifically adds these phosphate groups to the amino acid tyrosine within the proteins. The insulin receptor consists of two units that come together (dimerize) when they bind with insulin to form an active tyrosine kinase enzyme (fig. 11.11). Each unit of the receptor contains a site on the outside of the cell that binds to insulin (termed the ligand-binding site) and a part that spans the plasma membrane, with an enzymatic site in the cytoplasm. The enzymatic site is inactive until insulin binds to the ligand-binding site and causes dimerization of the receptor. When insulin binding and dimerization occur, the enzymatic

298 Chapter Eleven

Table 11.5 Sequence of Events Involving the Ca2+ Second-Messenger System

1. The hormone binds to its receptor on the outer surface of the target cell's plasma membrane.

2. Hormone-receptor interaction stimulates the activity of a membrane enzyme, phospholipase C.

3. Activated phospholipase C catalyzes the conversion of particular phospholipids in the membrane to inositol triphosphate (IP3) and another derivative, diacylglycerol.

4. Inositol triphosphate enters the cytoplasm and diffuses to the endoplasmic reticulum, where it binds to its receptor proteins and causes the opening of Ca2+ channels.

5. Since the endoplasmic reticulum accumulates Ca2+ by active transport, there exists a steep Ca2+ concentration gradient favoring the diffusion of Ca2+ into the cytoplasm.

6. Ca2+ that enters the cytoplasm binds to and activates a protein called calmodulin.

7. Activated calmodulin, in turn, activates protein kinase, which phosphorylates other enzyme proteins.

8. Altered enzyme activity mediates the target cell's response to the hormone.

Insulin

Insulin

Calmodulin Kinase Cascade

Binding to receptor proteins

Extracellular fluid

Extracellular fluid

Cytoplasm

Dimerization

Calmodulin Kinase Cascade

Phosphorylation of receptor

Tyrosine kinase now active

Phosphorylation of signal molecules

Cascade of effects

Phosphorylation of signal molecules

Cascade of effects

Glucose uptake and anabolic reactions

■ Figure 11.11 The receptor for insulin. Insulin binds to two units of its receptor protein, causing these units to dimerize (come together) on the plasma membrane. This activates the tyrosine kinase enzyme portion of the receptor. As a result, the receptor phosphorylates itself, thereby making the enzyme even more active. The receptor then phosphorylates a number of cytoplasmic "signal molecules" that exert a cascade of effects in the target cell.

site is activated in each unit of the receptor, and one unit phos-phorylates the other. This process, termed autophosphorylation, increases the tyrosine kinase activity of the dimerized receptor.

The activated tyrosine kinase receptor then phosphorylates other proteins that serve as signaling molecules. Some of these signaling molecules are themselves kinase enzymes that phos-phorylate and activate other second-messenger systems. As a result of a complex series of activations, insulin and the different growth factors regulate the metabolism of their target cells.

For example, insulin indirectly stimulates the insertion of GLUT-4 carrier proteins (for the facilitated diffusion of glucose; see chapter 6, fig. 6.15) into the plasma membrane of skeletal muscle, adipose, and liver cells. In this way, insulin stimulates the uptake of plasma glucose into these organs. Also, the binding of insulin to its receptor indirectly causes the activation of glycogen synthetase, the enzyme in liver and skeletal muscles that catalyzes the production of glycogen in these organs.

The complexity of different second-messenger systems is needed so that different signaling molecules can have varying effects. For example, insulin uses the tyrosine kinase second-messenger system to stimulate glucose uptake into the liver and its synthesis into glycogen, whereas glucagon (another hormone secreted by the pancreatic islets) promotes opposite effects—the hydrolysis of hepatic glycogen and subsequent secretion of glucose—by activating a different second-messenger system that involves the production of cAMP.

Test Yourself Before You Continue

1. Using diagrams, describe how steroid hormones and thyroxine exert their effects on their target cells.

2. Use a diagram to show how cyclic AMP is produced within a target cell in response to hormone stimulation and how cAMP functions as a second messenger.

3. Describe the sequence of events by which a hormone can cause a rise in the cytoplasmic Ca2+ concentration and explain how Ca2+ can function as a second messenger.

4. Explain the nature and actions of the receptor proteins for insulin and the growth factors.

Hypothalamus

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Responses

  • juhani lydman
    What second messenger does ca bind to?
    8 years ago
  • petronilla
    Does TSH use a 1st or 2nd messenger mechanism to exert it effect on t?
    8 years ago
  • jordan
    Can epinephrine act through two second messenger systems?
    8 years ago
  • codey white
    Is tyrosine kinase messenger system secondary?
    7 years ago
  • Jak
    How tyrosine kinase specifically activate the glut transpoter?
    4 years ago
  • pirkko
    How does epinephrine act through ip3 and camp?
    3 years ago
  • pierino
    What are the examples of hormones which use tyrosine kinase system?
    3 years ago
  • rezene
    Are there second messengers in tyrosine kinase?
    2 years ago
  • milo
    Which 3 hormones act via tyrosine kinase second messenger?
    2 years ago
  • iolanda
    What is the second messenger system used by growth factors?
    1 year ago
  • herbert
    What are the mechanism in which tyrosine kinase acts as a second mesenger?
    1 year ago
  • Margaret
    Which hormone use tyrosine kinase for it is action?
    1 year ago
  • esmeralda
    What messenger system does insulin use?
    6 months ago

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