14.12 : Intracellular Signaling Cascades

Intracellular signaling cascades amplify a signal originating extracellularly and directs it to its intended intracellular target resulting in transcription, translation, protein modifications, enzyme activation, cellular metabolism, mitosis, and/or apoptosis.

The most basic of signaling cascades involves the activation of second messengers and the release of kinases. Kinases activate or deactivate proteins and enzymes by adding a phosphate group to them. Phosphatases remove phosphate groups resulting in the deactivation or reactivation of proteins.

The cyclic AMP (cAMP) pathway is named for its second messenger, cAMP. This pathway is most often initiated when a ligand binds to a G-coupled protein receptor. The G-protein decouples from the receptor and triggers adenylate cyclase to synthesize cAMP from ATP. For each ligand-receptor interaction, multiple cAMP molecules are generated—amplifying the signal.

cAMP activates protein kinase A (PKA). PKA is a tetramer molecule with two regulatory subunits and two active subunits. When four cAMP molecules interact with a PKA molecule, it releases the two active subunits. These PKA subunits phosphorylate target proteins and enzymes. In the case of gene expression, PKA activates CREB, a transcription factor in the nucleus.

The steps that precede the intracellular signaling cascade that is the ligand and receptor—are referred to as upstream events. Those that come after the cAMP pathway—the phosphorylation of CREB in the above example—is referred to as a downstream event. There are numerous upstream and downstream events in which these pathways can be involved.

A more complex signaling cascade is that of the Ras-Raf-MAP Kinase pathway, which involves a series of sequential kinases activating other kinases. In this pathway Ras, a small GTPase enzyme, is activated when a growth factor binds to its receptor (the upstream event). Ras then activates Raf- or MAP kinase kinase kinase (MAP3K). MAP3K phosphorylates and thus activates another kinase- MAP kinase kinase (MAP2K, also called MEK). This kinase activates MAP kinase (MAPK, also called ERK) by phosphorylation. MAPK migrates to the nucleus where it can phosphorylate several transcription factors (downstream events). One such transcription factor is c-myc which initiates the transcription of the myc family of genes involved in cell proliferation and cancer. The Ras-Raf-MAP kinase pathway uses multiple kinases to amplify the external signal brought by growth factors and is more complex than the simpler cAMP pathway.

Other intracellular signal cascades, named for their second messengers, are the Phosphoinositol, Arachidonic acid, and Cyclic GMP systems.