BB Chapter 16

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Chapter 16:

Chapter 16 Cell Communication

Communication is “Key”:

Communication is “Key” Some examples: Bacteria in solution can detect the presence of other bacteria Yeast can signal to other yeast for mating In multicellular organisms communication is used for: Development Growth Healing Day to day

Example: Yeast Communicate to Reproduce:

Example: Yeast Communicate to Reproduce There are two varieties of Saccharomyces cerevisiae a-type a -type They can come together for sexual reproduction BUT it has to be an a-type with an a -type Two types that are the same cannot mate

Yeast Sexual Reproduction:

Yeast Sexual Reproduction How does an a-type know when an a -type is nearby??? (and vice versa)

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Communication - “Talking” : Yeast produce and secrete a signaling molecule = “Mating factor” a-type yeast produce a-factor a -type yeast produce a -factor

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Communication – “Listening”: Yeast have cell surface receptors for the opposite mating factor a-type yeast produce receptors for a -factor a -type yeast produce receptors for a-factor Mating factor binds to receptor on opposite cell type

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Transduction/Relay of Signal: Signal is conveyed to inside of cell Binding of mating factor causes a change in the receptor Change in receptor causes change inside of cell Response: Cells grow toward one another

The Schmoo!:

The Schmoo !

Cell Signaling Involves:

Cell Signaling Involves Production of a signaling molecule Detection of the signaling molecule by the target cell Signal transduction (relay of the signal) Response

KEY CONCEPT:

KEY CONCEPT Signal Transduction: “reading” a signal and relaying it throughout a cell.

Four Types of Signals:

Four Types of Signals Endocrine Via bloodstream (long distance) __________________ Generalized By endocrine cells

Four Types of Signals:

Four Types of Signals Paracrine _________________ Diffuse through ECM and affect nearby cells Sometimes the signal acts on the cell that made it (termed autocrine signaling)

Four Types of Signals:

Four Types of Signals Neuronal Via _________________ Long distance but directed to specific cells (via nerve terminals/synaptic junctions)

Four Types of Signals:

Four Types of Signals Contact Dependent By direct ____________________

Steps in Signaling (Expanded List):

Steps in Signaling (Expanded List) 1) synthesis of signal 2) release of signal 3) transport of signal 4) detection by target 5) response of target 6) removal of signal

How does a cell RECEIVE to a signal?:

How does a cell RECEIVE to a signal? Receptors!

How does a cell RESPOND to a signal?:

How does a cell RESPOND to a signal? Receptor signals to intracellular signaling molecules (acts like a relay). Modulates activity of some EFFECTOR PROTEIN (causes the cell’s response)

Different Types of Cells May Respond Differently to the Same Signal:

Different Types of Cells May Respond Differently to the Same Signal Depends on The receptor The intracellular signaling molecules The effector proteins

Different Types of Cells May Respond Differently to the Same Signal:

Different Types of Cells May Respond Differently to the Same Signal

Cellular Activities Depend on the Combination of Signals Received:

Cellular Activities Depend on the Combination of Signals Received

Cellular Responses Can Be Fast or Slow:

Cellular Responses Can Be Fast or Slow

KEY CONCEPT:

KEY CONCEPT Signal molecule : the LIGAND Binds to the Receptor: Triggers a conformational change that will affect cellular function.

Receptor Expression:

Receptor Expression Relatively LOW levels: typically 10 - 20,000 molecules/cell 0.0001 – 0.0002% of total protein actin > 10 7 molecules/cell

How many DIFFERENT receptors for each cell?:

How many DIFFERENT receptors for each cell? Many! But each cell has a DISTINCT SET.

Signal Transduction (In General):

Signal Transduction (In General) Signal binds receptor Change occurs in receptor Change in conformation Change in protein-protein interactions Alters activity of other proteins inside the cell Usually a relay Receptor → protein 1 → protein 2 → protein 3 → etc…

Molecular Switches Are Proteins That Can Be Turned On and Off:

Molecular Switches Are Proteins That Can Be Turned On and Off Signal causes conversion from inactive to active state (or vice versa) Two major classes: Activity depends on ___________________ state Activity controlled by binding to GTP (active) or GDP (inactive)

Phosphorylation:

Phosphorylation Kinases = Enzymes that add a phosphate group Serine/ threonine kinases Tyrosine kinases Phosphatases = Enzymes that remove a phosphate group

GTP-Binding Proteins:

GTP-Binding Proteins Inactive as long as bound to GDP Can be stimiulated to exchange GDP for GTP Active when bound to GTP

GTP-Binding Proteins:

GTP-Binding Proteins Have intrinsic GTPase activity Can switch themselves OFF by hydrolyzing GTP to GDP

SUMMARY: Signal Transduction:

SUMMARY: Signal Transduction A signal binds a receptor Transduction is a MULTI-STEP process NUMEROUS signals Response to a ligand VARIES

Receptor Locations:

Receptor Locations P lasma membrane Cytosol N ucleus

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Signals that rely on surface receptors = largest group Signal must be transmitted INSIDE by the receptor

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Signals that bind intracellular receptors are molecules that can enter the cell ________________ hormones _________________ hormones Some dissolved _______________

“Nuclear” Receptors:

“Nuclear” Receptors

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The glucocorticoid receptor!

Nitric Oxide:

Nitric Oxide Dissolved gas synthesized from arginine Acts as local signal Causes dilation of blood vessels via relaxation of smooth muscle cells lining them

Nitric Oxide:

Nitric Oxide Frequently acts through binding to GUANYLY CYCLASE Converts GTP to cyclic GMP (another signaling molecule)

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Cell Surface Receptors

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LIGAND RESPONSE SURFACE RECEPTOR

Cell Surface Receptors Must TRANSMIT the Signal Inward:

Cell Surface Receptors Must TRANSMIT the Signal Inward Receptor triggers a change inside the cell by interacting with intracellular signaling molecules Often, acts as a relay (signaling cascade)

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LIGAND RESPONSE SURFACE RECEPTOR MOLECULAR SWITCH

THREE MAIN CLASSES OF CELL SURFACE RECEPTORS:

THREE MAIN CLASSES OF CELL SURFACE RECEPTORS Ion-channel coupled receptors ( ligand gated ion channels!) G-protein coupled receptors Enzyme coupled receptors

Ion-Channel Coupled Receptors:

Ion-Channel Coupled Receptors Signal opens ion-channel This is the same as a ligand gated ion channel

Enzyme Coupled Receptors:

Enzyme Coupled Receptors Either act as enzymes or associate with enzymes inside the cell (activating them)

G-Protein Coupled Receptors:

G-Protein Coupled Receptors Receptor interacts with and activates a membrane-bound TRIMERIC GTP binding protein (G-protein)

G-Protein-Coupled Receptors (GPCRs):

G-Protein-Coupled Receptors (GPCRs) Largest family of cell-surface receptors “7-pass transmembrane receptor”

G-Proteins:

G-Proteins Consist of a , b , and g subunits Also called “ trimeric GTP binding proteins” (to distinguish from monomeric GTP- binding proteins) a and g subunits are linked to the cell membrane via lipid anchors

G-Proteins:

G-Proteins In un-stimulated state, a -subunit is bound to GDP (inactive) When stimulated, exchanges GDP for GTP (becomes active) Active G-proteins bind and affect activity of other proteins inside the cell

G-Proteins:

G-Proteins a -subunit has GTPase activity – eventually hydrolyzes GTP back to GDP, becomes inactive

Common Targets of G-Protein Coupled Receptors:

Common Targets of G-Protein Coupled Receptors Ion channels

Common Targets of G-Protein Coupled Receptors:

Common Targets of G-Protein Coupled Receptors Enzymes, such as Adenyly cyclase : Converts ATP to cyclic AMP Phospholipase C: Produces inositol triphosphate (IP 3 ) and diacylglycerol

Second Messengers :

Second Messengers Relays the signal onward (from the receptor to the target/effector molecules) AMPLIFIES the signal.

PowerPoint Presentation:

second messenger response

Sequence of Events for Activation of Enzymes by GPCRs:

Sequence of Events for Activation of Enzymes by GPCRs Ligand Receptor G-protein Target enzyme Second Messenger Response

Common Second Messengers:

Common Second Messengers Cyclic AMP ( cAMP ) Produced by an enzyme Inositol triphosphate (IP 3 ) Produced by an enzyme Diacylglycerol (DAG) Produced by an enzyme Ca ++ Released from the ER

cAMP:

cAMP

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cAMP turns ON protein kinase A (a.k.a. PKA, cyclic AMP dependent protein kinase )

KEY CONCEPT:

KEY CONCEPT PKA can: 1) phosphorylate serines / threonines on enzymes 2) phosphorylate gene regulatory proteins .

The Inositol Phospholipid Pathway:

The Inositol Phospholipid Pathway Some GPCRs activate an enzyme called Phospholipase C. Phospholipase C cleaves phosphatidyl inositol ( phospholipid on the cytoplasmic face of the cell membrane) Produces inositol triphosphate (IP3) & diacylglycerol (DAG)

The Inositol Phospholipid Pathway:

The Inositol Phospholipid Pathway

The Inosital Phospholipid Pathway:

The Inosital Phospholipid Pathway IP 3 is released into the cytosol DAG stays in the membrane

The Inosital Phospholipid Pathway:

The Inosital Phospholipid Pathway IP 3 travels to the ER, where it simulates opening of ligand gated Ca 2+ channels Ca 2+ is released from ER into cytosol

The Inosital Phospholipid Pathway:

The Inosital Phospholipid Pathway DAG and Ca2+ activate Protein Kinase C (PKC) PKC affects activity of downstream molecules

Other Signaling is Also Mediated By Ca2+:

Other Signaling is Also Mediated By Ca 2+ Ca2+ levels in cytoplasm are kept low by pumps Pump it OUT of the cell Pump it INTO the ER Generates a steep electrochemical gradient Increases in calcium levels can be simulated by many different mechanisms (not just GPCRs)

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Calcium’s Effects Many different things! Secretion of neurotransmitters Muscle contraction Embryonic development

Calcium’s Effects :

Calcium’s Effects Ca 2+ is a powerful cellular regulator. There are many “calcium responsive elements” Protein Kinase C ( PKC) Calmodulin Other proteins, such as troponin (in skeletal muscle)

Calcium/Calmodulin Dependent Kinases:

Combination of calcium and calmodulin activities a variety of kinases (called Ca 2+ / calmodulin dependent kinases , aka CaM kinases ) Calcium/ Calmodulin Dependent Kinases

Summary for GPCRs:

Summary for GPCRs 1. Ligand binds GPCR 2. Activates G-protein 3. G-protein activates targets, such as A) Adenyly cyclase (makes cAMP ) cAMP activates PKA PKA phosphorylates downstream targets B) Phospholipase C Cleaves phosphatidyl inositol (makes DAG and IP3) IP3 releases calcium Calcium and DAG activate PKC PKC phosphorylates downstream targets

Enzyme-Linked Receptors:

Enzyme-Linked Receptors Transmembrane proteins that EITHER Have a cytosolic domain that is catalytic OR Interact with an enzyme inside the cell

Enzyme-Linked Receptors:

Enzyme-Linked Receptors Tend to regulate cell growth, proliferation, and differentiation Also regulate cytoskeletal rearrangements, affecting cell shape and movement

Enzyme-Linked Receptors:

Enzyme-Linked Receptors Largest class is Receptor Tyrosine Kinases (RTKs).

RTKs:

RTKs Usually span the membrane as one a -helix Binding of ligand causes two RTKs to dimerize They phosphorylate each other Phosphorylated tyrosines act as binding site for other molecules, which assemble in complexes and mediate downstream effects

PowerPoint Presentation:

The activated RTK recruits many proteins. Eg: Ras – a monomeric GTP-binding protein. – activates a kinase signaling cascade . KEY CONCEPT

Ras and Mitogen Activated Protein Kinases:

Ras and Mitogen Activated Protein Kinases Mitogens are signals that promote cell proliferation Mitogen activates RTK RTK activates Ras Ras activates a family of kinases called Mitogen Activated Protein Kinases (MAPKs) MAPKS regulate cell proliferation, survival, & differentiation (i.e. “cell fate” decisions) MAPKs Include MAP kinase kinase kinase MAP kinase kinase MAP kinase

Ras:

Ras Activating mutations in Ras are associated with ~30% of human cancers

More About RTKs:

More About RTKs RTKs can activate phosphoinositide-3-kinase (PI3K) Phosphorylates inositol phospholipids in the plasma membrane Inositol phospholipids serve as docking sites for other proteins including AKT – a kinase Promotes growth and survival of many cell types AKT also activates TOR (another kinase ) – encourages cells to get BIGGER TOR = “target of rapamycin ”

PI 3-kinase and Akt:

PI 3-kinase and Akt

Akt Promotes Cell Survival By Inhibiting Apoptosis:

Akt Promotes Cell Survival By Inhibiting Apoptosis

TOR Promotes Cell Growth (bigger!):

TOR Promotes Cell Growth (bigger!)

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Some signaling mechanisms DO NOT require a long signaling cascade!

JAKs and STATS :

JAKs and STATS Abbreviated signaling pathway that affects transcription JAKs = tyrosine kinases When activated, they activate STATs STATs go to the nucleus and alter gene expression STAT = s ignal t ransducer and a ctivator of t ranscription Held in an inactive state in absence of a signal Receptor → JAK → STAT → Transcription

KEY CONCEPT:

KEY CONCEPT Cells respond to many different signals. Pathways converge to produce the appropriate response. “modulation” “cross-talk”

How are Pathways Turned OFF?:

How are Pathways Turned OFF? Ligand is metabolized Receptor is degraded or sequestered Second messenger is metabolized Target proteins are dephosphorylated

PowerPoint Presentation:

Ligand activates a receptor. Receptor transduces the signal. G-proteins can relay the signal to membrane-bound enzymes that generate second messengers. Receptors themselves can have enzymatic activity. Intracellular receptors act as transcriptional activators SUMMARY

SUMMARY:

SUMMARY Second messengers generally activate kinases . Phosphorylation can lead to immediate ACTIVATION or DEACTIVATION of a cellular enzyme ( short-term ).

SUMMARY:

SUMMARY Phosphorylation can lead to changes in gene expression ( long-term ). Cascades are turned off by: metabolism of ligand sequestering of receptors breakdown of 2 nd messenger dephosphorylation