SIGNAL TRANSDUCTION PATHWAYS LINK SIGNAL RECEPTION WITH CELLULAR RESPONSE Cells communicate by generating, transmitting and receiving chemical signals

Cascade of Molecular Interactions Relay molecules – often proteins, transmit the signal from the receptor to the final cellular response Message is sent by phosphorylating and dephosphorylating protiens (results in shape changes) Phosphorylation done by kinases – activating Dephosphorylation done by phophatases - deactivating Phosphorylation Cascade

Cascade of Molecular Interactions Second messengers – water soluble molecules and / or ions can be involved in the transduction of messages from signal to cellular response Second messengers are often essential to the function of cascade Small / water soluble = rapid diffusion thru cells

Illustrative Example: cyclic AMP (cAMP) as a second messenger First messenger (i.e. epinephrine) triggers G-protein receptors Receptor protein triggers adenylyl cyclase which catalyses Rapid synthesis of many c AMP molecules from Atp molecules High c amp concentrations are quickly reduced by phosphodiesterase (which converts c AMP to AMP) Repeated stimulation by first messenger is required to maintain high concentrations of c amp in cytoplasm High levels of c AMP trigger the activation of kinases that eventually bring about the cellular response

Illustrative Example: calcium (Ca 2+ ) ions and inositol triphosphate (IP 3 ) as a second messengers Calcium is more widely used than cAMP as a second messenger Ca 2+ used with G-protein receptors and tyrosine kinase pathways Good secondary messenger because the concentration of Ca 2+ is usually very low (it is actively pumped out of cytoplasm either into extra cellular fluid, into ER, or into mitochondria) IP3 is another secondary messenger which can stimulate the release of Ca 2+

Cellular Response Nuclear Responses  Many signaling pathways regulate protein synthesis by turning a gene on or off  Phosphorylation cascades can end by activating or inactivating a transcription factor

Cellular Response Cytoplasmic Response  Signaling pathways regulate the activity of proteins found in the cytosol  For example: Epinephrine stimulating the breakdown of glycogen via signal transduction

Specificity of cell signaling The particular protiens a cell possesses determine what signaling molecules it responds to and the nature of the response. 4 different cells each respond to the same signaling molecule in a different way Signaling molecule Receptor Relay molecules Response 1 Cell A. Pathway leads to a single response. Response 2 Response 3 Cell B. Pathway branches, leading to two responses. Response 4 Response 5 Activation or inhibition Cell C. Cross-talk occurs between two pathways. Cell D. Different receptor leads to a different response.

Apoptosis integrates multiple cell-signaling pathways Apoptosis – programmed cell death; cellular agents chop up the DNA, fragment the organelles & other cellular components; the cell shrinks and becomes lobed (blebbing); cell parts are packaged up in vesicles that are engulfed & digested by specialized scavenger cells

Apoptosis controlled by signal transduction pathways Study of soil worm (Caenorhabditis elegan) reveal that there are cell death genes and cell death proteins (Ced -3 and Ced-4) that are always present in the cell in the inactive form. These proteins can be “turned on or off” by signal transduction pathways that Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Receptor for death- signaling molecule Ced-4 Ced-3 Inactive proteins (a) No death signal Ced-9 (inactive) Cell forms blebs Death- signaling molecule Other proteases Active Ced-4 Active Ced-3 Nucleases Activation cascade (b) Death signal

Apoptosis Caspases are the main proteases (enzymes that cut up proteins) that carry out apoptosis Apoptosis can be triggered by:  An extracellular death-signaling ligand  DNA damage in the nucleus  Protein misfolding in the endoplasmic reticulum Apoptosis may be involved in some diseases (for example, Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers

Apoptosis evolved early in animal evolution and is essential for the development and maintenance of all animals Interdigital tissue 1 mm