Overview: Cellular Messaging

                  Cell-to-cell communication is essential for both multicellular and unicellular organisms

                  Biologists have discovered some universal mechanisms of cellular regulation

                  Cells most often communicate with each other via chemical signals

                  For example, the fight-or-flight response is triggered by a signaling molecule called epinephrine


Concept 11.1: External signals are converted to responses within the cell

                  Microbes provide a glimpse of the role of cell signaling in the evolution of life


Evolution of Cell Signaling

                  The yeast, Saccharomyces cerevisiae, has two mating types, a and a

                  Cells of different mating types locate each other via secreted factors specific to each type

                  A signal transduction pathway is a series of steps by which a signal on a cell’s surface is converted into a specific cellular response

                  Signal transduction pathways convert signals on a cell’s surface into cellular responses

                  Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and were modified later in eukaryotes

                  The concentration of signaling molecules allows bacteria to sense local population density


Local and Long-Distance Signaling

                  Cells in a multicellular organism communicate by chemical messengers

                  Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells

                  In local signaling, animal cells may communicate by direct contact, or cell-cell recognition

                  In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances

                  In long-distance signaling, plants and animals use chemicals called hormones

                  The ability of a cell to respond to a signal depends on whether or not it has a receptor specific to that signal


The Three Stages of Cell Signaling: A Preview

                  Earl W. Sutherland discovered how the hormone epinephrine acts on cells

                  Sutherland suggested that cells receiving signals went through three processes





Concept 11.2: Reception: A signaling molecule binds to a receptor protein, causing it to change shape

                  The binding between a signal molecule (ligand) and receptor is highly specific

                  A shape change in a receptor is often the initial transduction of the signal

                  Most signal receptors are plasma membrane proteins


Receptors in the Plasma Membrane

                  Most water-soluble signal molecules bind to specific sites on receptor proteins that span the plasma membrane

                  There are three main types of membrane receptors

              G protein-coupled receptors

              Receptor tyrosine kinases

              Ion channel receptors

                  G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors

                  A GPCR is a plasma membrane receptor that works with the help of a G protein

                  The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive

                  Receptor tyrosine kinases (RTKs) are membrane receptors that attach phosphates to tyrosines

                  A receptor tyrosine kinase can trigger multiple signal transduction pathways at once

                  Abnormal functioning of RTKs is associated with many types of cancers

                  A ligand-gated ion channel receptor acts as a gate when the receptor changes shape

                  When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor


Intracellular Receptors

                  Intracellular receptor proteins are found in the cytosol or nucleus of target cells

                  Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors

                  Examples of hydrophobic messengers are the steroid and thyroid hormones of animals

                  An activated hormone-receptor complex can act as a transcription factor, turning on specific genes


Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell

                  Signal transduction usually involves multiple steps

                  Multistep pathways can amplify a signal: A few molecules can produce a large cellular response

                  Multistep pathways provide more opportunities for coordination and regulation of the cellular response


Signal Transduction Pathways

                  The molecules that relay a signal from receptor to response are mostly proteins

                  Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated

At each step, the signal is transduced into a different form, usually a shape change Protein Phosphorylation and Dephosphorylation

                  In many pathways, the signal is transmitted by a cascade of protein phosphorylations

                  Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation

                  Protein phosphatases remove the phosphates from proteins, a process called dephosphorylation

                  This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off or up or down, as required


Small Molecules and Ions as Second Messengers

                  The extracellular signal molecule (ligand) that binds to the receptor is a pathway’s “first messenger”

                  Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion

                  Second messengers participate in pathways initiated by GPCRs and RTKs

                  Cyclic AMP and calcium ions are common second messengers


Cyclic AMP

                  Cyclic AMP (cAMP) is one of the most widely used second messengers

                  Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal

                  Many signal molecules trigger formation of cAMP

                  Other components of cAMP pathways are G proteins, G protein-coupled receptors, and protein kinases

                  cAMP usually activates protein kinase A, which phosphorylates various other proteins

                  Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl cyclase


Calcium Ions and Inositol Triphosphate (IP3)

                  Calcium ions (Ca2+) act as a second messenger in many pathways

                  Calcium is an important second messenger because cells can regulate its concentration

                  A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol

                  Pathways leading to the release of calcium involve inositol triphosphate (IP3) and diacylglycerol (DAG) as additional second messengers


Concept 11.4: Response: Cell signaling leads to regulation of transcription or cytoplasmic activities

                  The cell’s response to an extracellular signal is sometimes called the “output response”


Nuclear and Cytoplasmic Responses

                  Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities

                  The response may occur in the cytoplasm or in the nucleus

                  Many signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus

                  The final activated molecule in the signaling pathway may function as a transcription factor

                  Other pathways regulate the activity of enzymes rather than their synthesis

                  Signaling pathways can also affect the overall behavior of a cell, for example, changes in cell shape


Fine-Tuning of the Response

                  There are four aspects of fine-tuning to consider

              Amplification of the signal (and thus the response)

              Specificity of the response

              Overall efficiency of response, enhanced by scaffolding proteins

              Termination of the signal


Signal Amplification

                  Enzyme cascades amplify the cell’s response

                  At each step, the number of activated products is much greater than in the preceding step


The Specificity of Cell Signaling and Coordination of the Response

                  Different kinds of cells have different collections of proteins

                  These different proteins allow cells to detect and respond to different signals

                  Even the same signal can have different effects in cells with different proteins and pathways

                  Pathway branching and “cross-talk” further help the cell coordinate incoming signals


Signaling Efficiency: Scaffolding Proteins and Signaling Complexes

                  Scaffolding proteins are large relay proteins to which other relay proteins are attached

                  Scaffolding proteins can increase the signal transduction efficiency by grouping together different proteins involved in the same pathway

                  In some cases, scaffolding proteins may also help activate some of the relay proteins


Termination of the Signal

                  Inactivation mechanisms are an essential aspect of cell signaling

                  If ligand concentration falls, fewer receptors will be bound

                  Unbound receptors revert to an inactive state


Concept 11.5: Apoptosis integrates multiple cell-signaling pathways

                  Apoptosis is programmed or controlled cell suicide

                  Components of the cell are chopped up and packaged into vesicles that are digested by scavenger cells

                  Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells


Apoptosis in the Soil Worm Caenorhabditis elegans

                  Apoptosis is important in shaping an organism during embryonic development

                  The role of apoptosis in embryonic development was studied in Caenorhabditis elegans

                  In C. elegans, apoptosis results when proteins that “accelerate” apoptosis override those that “put the brakes” on apoptosis


Apoptotic Pathways and the Signals That Trigger Them

                  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 evolved early in animal evolution and is essential for the development and maintenance of all animals

                  Apoptosis may be involved in some diseases (for example, Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers