Lecture 10 Cell Communication Chapter 9

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Cell-Cell Interactions

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Cell CommunicationCommunication between cells requires:

ligand: the signaling molecule

receptor protein: the molecule to which the receptor binds- may be on the plasma membrane or within the cell

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Cell Signaling

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Cell Signals

Direct contactParacrine signalingEndocrine signaling

hormonesSynaptic signaling

neurotransmitters

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Cell Communication

Direct contact – molecules on the surface of one cell are recognized by receptors on the adjacent cell

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Cell Communication

Paracrine signaling – signal released from a cell has an effect on neighboring cells

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Cell Communication

Endocrine signaling – hormones released from a cell affect other cells throughout the body

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Cell Communication

Synaptic signaling – nerve cells release the signal (neurotransmitter) which binds to receptors on nearby cells

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Signal transductionEvents within the cell that occur in response

to a signalWhen a ligand binds to a receptor protein,

the cell has a responseDifferent cell types can respond differently to

the same signalEpinephrine example

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Cell Communication

A cell’s response to a signal often involves activating or inactivating proteins.

Phosphorylation is a common way to change the activity of a protein.

protein kinase – an enzyme that adds a phosphate to a protein

phosphatase – an enzyme that removes a phosphate from a protein

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Protein Phosphorylation

Two classes: serine/threonine kinases or tyrosine kinases

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Receptor ProteinReceptor proteins have a three-dimensional shape that fits

a specific signal molecule.When a signal molecule and receptor protein bind, a change

in the receptor protein is induced and a response in the cell is generated.

There is a conformational change that arises from the ligand binding to the receptor

Receptor-ligand complex can directly or indirectly interact with a whole host of other signaling molecules within the cell

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Receptor TypesReceptors can be defined by their location.

intracellular receptor – located within the cell

cell surface receptor or membrane receptor – located on the plasma membrane to bind a ligand outside the cell

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Cell Surface Receptors

There are 3 subclasses of membrane receptors:1. channel linked receptors – ion channel that opens in

response to a ligand2. enzymatic receptors – receptor is an enzyme that is

activated by the ligand3. G protein-coupled receptor – a G-protein (bound to

GTP) assists in transmitting the signal

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Cell Surface Receptors

Chemically gated ion channels

GPCR

Enzymatic receptors

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G proteinsRas and Trimeric G proteinRas is monomericTrimeric has 3 subunits – alpha, beta and

gammaBoth of them bind GTP in their active form

and bind GDP in their inactive form

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G-Protein Coupled Receptors

G-protein – protein bound to GTP or GDPG protein exists in two forms – active ( GTP bound) and

inactive (GDP bound)G protein is trimeric (3 subunits – alpha, beta , and gamma)The guanine nucleotide is bound to the alpha subunitG-protein-coupled receptor (GPCRs) – receptors bound to G

proteins- G-protein is a switch turned on by the receptor- G-protein then activates an effector protein (usually an

enzyme)

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G-Protein Coupled Receptors

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G-Protein Coupled ReceptorsOnce activated, the effector protein produces a second

messenger.- second messenger generates the cellular response to the

original signalFor example – one common effector protein is adenylyl cyclase

which produces cAMP as a second messenger.cAMP binds to Protein Kinase A and activates itAnother common effector protein is PhospholipaseC

PIP2 is acted on by effector protein phospholipase CProduces IP3 ( Inositol Tris phosphate) plus DAG(Diacyl glycerol)Both act as second messengers

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cAMP Signaling Pathway

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Calcium Ca2+ serves widely as

second messengerIntracellular levels

normally lowExtracellular levels

quite highEndoplasmic

reticulum has receptor proteins that act as ion channels to release Ca2+

Most common receptor binds IP3

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Amplifying the Signal

Most signaling molecules exist in such low concentration, diffusion across the cytoplasm requires amplification.A single cell surface receptor can stimulate a cascade of

protein kinases to amplify the signal. causes a strong response inside the cell to a weak signal outside

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Different receptors can produce the same second messengers

Hormones glucagon and epinephrine can both stimulate liver cells to mobilize glucoseDifferent signals, same effectBoth act by same signal transduction pathway

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Single signaling molecule can have different effects in different cells

Existence of multiple forms of the same receptor (subtypes or isoforms)

Receptor for epinephrine has 9 isoformsEncoded by different genesSequences are similar but differ in their

cytoplasmic domainsDifferent isoforms activate different G

proteins leading to different signal transduction pathways

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Intracellular Receptors

A steroid hormone receptor has three functional domains:1. hormone-binding domain2. DNA binding domain3. domain that interacts with co-activators to affect gene

expression

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Intracellular Receptors

Intracellular receptors are located within the cell, and trigger a variety of responses, depending on the receptor.acting as gene regulatorsacting as enzymes

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DNA binding site blocked

Transcriptionactivatingdomain

DNA binding site exposed

CortisolInhibitor

Signal molecule-binding domain

Regulation of Gene Transcription by Intracellular Receptors

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Intracellular Receptors

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CoactivatorsTarget cell’s response to a lipid-soluble cell

signal can vary enormously, depending on the nature of the cell

Even the same type of cell may have different responses

Depends on coactivators present Estrogen has different effects in uterine

tissue than mammary tissueNot presence or absence of receptorPresence or absence of coactivator

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Receptor Kinases (receptors with enzymatic function)receptor tyrosine kinases - membrane receptor- when bound by a ligand, the receptor is activated by

dimerization and autophosphorylation- activated receptor adds a phosphate to tyrosine on a

response protein- an example is the insulin receptor

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Activation of Receptor Tyrosine Kinase

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Insulin receptorActivated receptor

has phosphorylated sites that allow docking

Insulin is a hormone that helps to maintain a constant blood glucose level

Lowers blood glucose

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Kinase cascadeMitogen-activated protein (MAP) kinases

Important class of cytoplasmic kinasesMitogens stimulate cell divisionActivated by a signaling module called a

phosphorylation cascade or kinase cascadeSeries of protein kinases that phosphorylate

each other in successionAmplifies the signal because a few signal

molecules can elicit a large cell response

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Ras proteinsSmall GTP-binding protein (G protein)Link between the RTK and the MAP kinase

cascadeRas protein is mutated in many human

tumors, indicative of its central role in linking growth factor receptors to their cellular response

Ras can regulate itself – stimulation by growth factors is short-lived

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Scaffold proteinsThought to organize the

components of a kinase cascade into a single protein complex

Binds to each individual kinase such that they are spatially organized for optimal function

Benefit in efficiancyDisadvantage in

reducing amplification effect

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Expression of Cell Identity

Cells contain an array of marker proteins located on the cell surface.glycolipids - tissue-specific cell surface markersMajor histocompatibility complex (MHC) proteins -

identify self versus non-self cells