Signal-Transduction Pathways

By Haylee Sonnenberg

When signal receptors are plasma-membrane proteins, the transduction stage of cell signaling is usually a multi-step pathway. Multi-step pathway benefits:

Signal amplification: large number of activated molecules at the end. More opportunities for coordination and regulation.

Pathways relay signals from receptors to cellular responses

The binding of a specific extracellular signal molecule to a receptor in the plasma membrane sparks step #1 in the molecular interactions chain—the signal-transduction pathway—that leads to a particular response within the cell. It’s just like falling dominoes: the signal-activated receptor activates another protein which activates another molecule, and so on, until the last protein is activated. Relay molecules: the molecules that relay a signal from receptor to response [mostly proteins]. Interactions of proteins are HUGE in cell signaling and regulation. Remember: the original signal molecules are NEVER physically passed down the pathway; the information is passed down. At each step the signal changes form [usually a conformational protein change brought on by phosphorylation].

Protein phosphorylation, a common mode of regulation in cells, is a major mechanism of signal transduction

Protein kinase: the general name for an enzyme that transfers phosphate groups from ATP to a protein. Most cytoplasmic protein kinases don’t act on themselves, but on other substrate proteins. They also phosphorylate their substances on either of 2 amino acids: serine or threonine. Many relay molecules in signal-transduction pathways are protein kinases, and often act upon each other.

A phosphorylation cascade

Protein phosphorylation, a common mode of regulation in cells, is a major mechanism of signal transduction

Protein kinases are über important: 1% of our genes are codes to make kinases. 1 cell alone has hundreds of different kinds, each with specificity for a different substrate protein. Together, they regulate a large proportion of the 1000’s of proteins in a cell. Abnormal activity of a kinase = abnormal cell growth and cancer.

For a cell to normally respond to an extracellular signal, it must have mechanisms for turning off the signal-transduction pathway when the initial signal is no longer present. Protein phosphatases: enzymes that remove phosphate groups from proteins. The activity of a protein regulated by phosphorylation depends on the balance in the cell between active kinase and active phosphatase molecules. When the extracellular signal molecule isn’t there, active phosphatase molecules prevail, and the signaling pathway and cellular response turn off.

Certain small molecules and ions are key components of signaling pathways

[second messengers]

Not all components of signal-transduction pathways are proteins. A lot of signaling pathways also consist of small, non-protein, water-soluble molecules or ions, called second messengers. [The extracellular signal molecule that binds to the membrane receptor is a pathway’s first messenger.] Since second messengers are small and water-soluble, they can easily disperse throughout the cell by diffusion. Second messengers take part in pathways initiated by G-protein-linked receptors and tyrosine-kinase receptors. The 2 most popular second messengers are cyclic AMP and calcium ions [Ca2+]. Most relay proteins are sensitive to the cytosolic concentration of either one or the other of these second messengers.

Certain small molecules and ions are key components of signaling pathways

[second messengers]Cyclic AMP The moment Earl Sutherland had established that epinephrine somehow causes glycogen to break down without passing through the plasma membrane, the search began for the second messenger that transmits the signal from the plasma membrane to the metabolic machinery in the cytoplasm. He found that the binding of epinephrine to the plasma membrane of a liver cell raises the cytoplasmic concentration of cyclic adenosine monophosphate, abbreviated cyclic AMP or cAMP.

Cyclic AMP

Certain small molecules and ions are key components of signaling pathways

[second messengers]Cyclic AMP An enzyme built into the plasma membrane, adenylyl cyclase, converts ATP to cAMP in response to an extracellular signal [epinephrine in this case]. Adenylyl cyclase only becomes active after epinephrine binds to a specific receptor protein. So, the first messenger, the hormone, causes a membrane enzyme to synthesize cAMP, which then sends the signal to the cytoplasm. The cAMP doesn’t last long without the hormone, because another enzyme converts the cAMP into AMP, which is an inactive product. Another surge of epinephrine is required to raise the cytosolic concentration of cAMP again. Other hormones and signal molecules besides epinephrine trigger cAMP pathways, like G proteins, G-protein-linked receptors, and protein kinases.

cAMP as a second messenger

Certain small molecules and ions are key components of signaling pathways

[second messengers]Cyclic AMP Protein kinase A, a serine/threonine kinase, is usually the relay molecule immediately after cAMP in a signaling pathway. cAMP activates this kinase. The active kinase then phosphorylates other proteins in the cell. G-proteins inhibit adenylyl cyclase. For these systems, a different signal molecule activates a different receptor, which then activates an inhibitory G protein. Certain microbes cause disease. Take cholera, for example. People acquire Vibrio cholerae, the cholera bacteria, from bad drinking water. The bacteria colonizes the small intestine lining and produces a toxin, which for cholera is an enzyme that chemically changes a G protein involved in regulating salt and water secretion. Since the modified G protein is now unable to hydrolyze GTP to GDP, it stays forever stuck in its active form, continuously causing adenylyl cyclase to make cAMP. The high concentration of cAMP causes a high secretion of water and salts into the intestines. In the end, the infected person develops horrible diarrhea and can die if untreated from salt and water depletion.

Certain small molecules and ions are key components of signaling pathways

[second messengers]Calcium Ions and Inositol Trisphosphate Many signal molecules in animals cause responses in their target cells via signal-transduction pathways that increase the cytosolic concentration of calcium ions. Ca2+ are even more widely used than cAMP as a second messenger. Raising the cytosolic Ca2+ concentration causes many responses in animal cells [muscle cell contraction, secretion of certain substances, and cell division]. In plant cells, Ca2+ act as a second messenger in signaling pathways for coping with environmental stresses, like drought or cold. Cells use Ca2+ as a second messenger in G-protein pathways and tyrosine-kinase receptor pathways. Although cells always contain some Ca2+, this ion can function as a second messenger because its concentration in the cytosol is normally much lower than in the cell.

Certain small molecules and ions are key components of signaling pathways

[second messengers]Calcium Ions and Inositol Trisphosphate Ca2+ are actively transported out of the cell and are actively imported from the cytosol into the ER [sometimes even into mitochondria and chloroplasts]. Because of this, the calcium concentration in the ER is usually much higher than in the cytosol.

Calcium ion concentrations in an animal cell

Certain small molecules and ions are key components of signaling pathways

[second messengers]Calcium Ions and Inositol Trisphosphate Because the cytosolic calcium level is low, a small change in the number of ions represents a relatively large percentage change in calcium concentration. In response to a signal relayed by a signal-transduction pathway, the cytosolic calcium level may rise, usually by a mechanism that releases Ca2+ from the cell’s ER. The pathways leading to calcium release involve yet other second messengers, diacylglycerol (DAG) and inositol trisphosphate (IP3). These 2 messengers are produced by a split of a certain kind of phospholipid in the plasma membrane.

Calcium and inositol trisphosphate in signaling pathways

Certain small molecules and ions are key components of signaling pathways

[second messengers]Calcium Ions and Inositol Trisphosphate Because IP3 acts before calcium in the pathway, calcium could be considered a third messenger. However, the term second messenger is used for all small, non-protein components of signal-transduction pathways. Sometimes, Ca2+ activate a signal-transduction protein directly, but often they function by means of calmodulin, a Ca2+-binding protein present at high levels in eukaryotic cells. Calmodulin mediates many calcium-regulated processes in cells. When calcium ions bind to it, calmodulin changes conformation and then binds to other proteins, activating or inactivating them. The proteins most often regulated by calmodulin are protein kinases and phosphatases—the most common relay proteins in signaling pathways.

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