Cell CommunicationChapter 11

Recent Nobel Prizes in Medicine

• 2001 – Hartwell, Hunt, & Nurse – cyclin pathways and cell cycle regulation (yeast)

• 2002 – Brenner, Sulston, Horvitz – used C. elegans to elucidate the mechanism of apoptosis

• 2006 – Fire & Mello - used C.elegans to discover the pathway of RNA interference

Simon Sez…

• Signaling is a lot like the game “Simon Says…”

• The signal is received: the game players hear: “Simon says take a step forward”

• The signal is transduced: players must decide whether to step forward or not

• The signal elicits a response: players step forward if the command was preceded by “Simon says”

3 Stages of Signaling

• Thesis: external signals are received & converted to responses within the cell

1. Reception• Signaling molecule binds to receptor protein =

Shape Change

2. Transduction• Cascades of molecular interactions relay signals

from receptor proteins to target molecules in the cell

3. Response• Regulation of transcription or cytoplasmic activities

Cell-to-Cell Communication

• Critical for multicellular organisms

• Trillions of cells must communicate in order to coordinate their activities

• Recently, research is indicating how this communication can be corrupted, and cancer may occur

• Although fairly unimportant for the AP Exam, crucial for understanding the breakthroughs in cancer and genetics that are occurring almost monthly now

Commonality?

• The same set of cell signaling mechanisms show up:

1. Embryonic development

2. Hormone action• Viagra’s effects are mediated through a STP (signal

transduction pathway) called “cGMP Pathway”

3. Physiology• Cascades are responsible for blood vessel dilation

& inflammatory response in allergic rxns

4. Oncogenesis (Onco- means cancer)• Cyclin pathway & Oncoproteins

11.1 Introduction

• Cell Signaling was probably 1st for mating between microorganisms• We can look at bacteria (Saccharomyces

cerevisiae)• Responsible for bread, wine, & beer• 2 Mating Types (a and α)• When their mating factors bind to an external

receptor on the other mating type, the cells will grow closer together

• Eventually, the cells fuse together (mating)• Results in an new cell that is genetic different

from either mating type

Mechanism?

• The signal at the cell surface gets transformed into a cellular response (mating), but how?

• Signal Transduction Pathway (STP)

• The mechanism of the STP in prokaryotes and complex mammals is strikingly identical

Local vs. Long-Distance

• Sometimes there is direct contact

• Other times, signals travel a short distance

• Called Local Regulators• Influence cells in the vicinity• Example, growth factors – compounds that

stimulate nearby target cells to grow & divide

• Examples include Paracrine & Synaptic signaling

Long Distance Signaling

• Hormones (Endocrine Signals)• Endocrinologists study??

• Hormones travel by circulatory system vessels

• Hormones vary widely in size

• Another example, signal transmission along the length of a neuron

Long-Distance Signaling

Overview of Cell Signaling

3 Stages of Cell Signaling

1. Reception• Target cell detects a signaling molecule coming

from outside the cell• Cell surface receptor protein binds the signal

molecule

2. Transduction• Signal molecule binds and causes conformational

change in the surface receptor protein, which initiates the signal transduction pathway

• Sometimes STP is a single step, but mostly multiple steps compose a STP

3 Steps of Cell Signaling

11.2 - Reception

• Reception involves getting the signal to the correct receiver• Think of talking on a bus, others may hear, but

you only want your listener to get the full message

• Signaling molecules are complementary in shape to the receptor molecule• Signaling molecule sometimes called ligand

• Molecule that specifically binds to another larger molecule

Reception (Page 2)

• Usually receptor-ligand binding causes a conformational change in the receptor molecule• The conformational change activates the

receptor & initiates a cascade event or STP

• Can be likened to allosteric regulation of an enzyme• Shape change at one site = promotion/inhibition

of enzyme activity

2 Types of Signal Receptors

• 1. Plasma Membrane Receptors• G Protein-Coupled Receptors• Receptor Tyrosine Kinase• Ion Channel Receptors

• 2. Intracellular Receptors• Chemical messengers that pass through

membrane• Steroid & thyroid hormones• Tend to carry out complete signal transduction by

themselves

G Protein-Coupled Receptor (GPCR)

• Def. – Plasma membrane receptor that works with the help of a G protein• G protein – protein that binds GTP

• Common receptor

• Found in yeast mating factors, epinephrine, & assorted other hormones & neurotransmitters

• Also responsible for the symptoms of many bacterial diseases, such as cholera & botulism

• Similarity between prokaryotes and eukaryotes evidences early evolution of G protein receptor molecules

• 60% of all meds exert their influence by G protein pathways

G Protein-Coupled Receptors (Page 2)

• All G Proteins have same basic structure• 7 α-helices spanning the membrane• Loops on either face of the membrane for binding

sites

G Protein-Coupled Receptor

Signaling molecule binds, causing conformational change in receptor. Inactive G protein binds & is activated by GTP formation.

G Protein also functions as an GTPase, so makes itself inactive in the absence of continuing signals

Receptor Tyrosine Kinase (RTK)

• Enzymatic activity

• Kinase – enzyme that catalyzes transfer of phosphate group

• Here, Phosphate is transferred from ATP to Tyrosines (type of amino acid)

• Rapid amplification• 1 tyrosine kinase complex can activate 10 or

more STPs or cellular responses

Receptor Tyrosine Kinase

Dimerization

Ion Channel Receptor

• Membrane receptor with a region that acts as a “gate” when the receptor changes shape.

• When the signal molecule binds, gate opens or closes• Allows or blocks flow of specific ions• Such as Na+ or Ca2+

• Important in the nervous system • Neurotransmitters & synaptic transmission• Could be controlled by electrical signals instead of

chemicals (Voltage-gated ion channels)

Ion Channel Receptor

Intracellular ReceptorTestosterone

-- Example of steroid

Most intracellular receptor signals do the entire transduction on their own

Testosterone behaving as a transcription factor

-- controls which genes (DNA) are transcribed into mRNA

11.3 Transduction

• Multistep Pathway

• Signal amplification• One molecule in the series,

passes signal to multiple molecules

of the next component• Think of dominoes

• Small Signal amount Large cellular response

Amplification & Pathways

11.3 Transduction (Page 2)

• Incoming signal is NOT physically passed along a signaling pathway

• Certain information is passed on

• By transduction (change form) into a different form of each protein in the cascade

• Typically transduction brought about by phosphorylation (remember from CH8?)

11.3 Transduction (Page 3)

• Signal Transduction Pathways often involve a phosphorylation cascade• A series of different molecules in a pathway are

phosphorylated in turn, each molecule adding a phosphate group to the next one in line

• As each molecule is phosphorylated, it becomes active

• As each molecule transfers the phosphate, it becomes inactive again

• Involves enzymes called protein kinases• General term for an enzyme that transfers

phosphate from ATP to a protein

Phosphorylation Cascade

Protein Kinases

• Phosphorylation & dephosphorylation of proteins is the primary mechanism of cellular activity regulation

• 2% of genomic content codes for protein kinases

• Abnormal kinase activity leads to cancer

• Protein Phosphatases• Enzymes that remove phosphate from proteins• Recycles pathway components

GF = Growth factor

RTK = Receptor Tyrosine Kinase

Ras = G Protein -- Associated with tumor growth

Rho = G protein

Traf = Tumor necrosis factor

RTK = Receptor Tyrosine Kinase

GPCR – G-protein coupled receptor

Apoptosis = Programmed cell death

PDK1 = Protein dehydrogenase kinase

Akt = Protein kinase -- Involved in apoptosis

Second Messengers

• Capable of initiating phosphorylation cascade on their own

• Signal pathway members that are nonprotein, small, and water-soluble • Cyclic AMP or Calcium ions

• Called 2nd since the membrane receptor is called 1st messenger

• 1st messenger can only be RTK or GPCR

Cyclic AMP

Epinephrine (First Messenger) 1. Binds to GPCR

2. Activates G protein

3. Adenylyl cyclase converts ATP cyclicAMP

-- Since 1 GPCR can affect multiple G proteins, the epinephrine signal is amplified through this pathway

Why would epinephrine want its signal amplified?

Zimbabwe’s Cholera Epidemic

• We can explain how (vibrio cholera) actually creates its symptoms

• Cholera bacteria (ingested via infected H2O) secretes an enzyme (toxin) that modifies G protein

• This G protein regulates cell tonicity and water secretion• Toxin interferes with GTP conversion (deactivation)• So GTP keeps activating adenylyl cyclase

cyclicAMP• Water and salt secretion continues when it should

have shut off long ago• Amplification?

• Patients require significant rehydration to compensate for fluid and electrolyte loss

Calcium Ions

• More common 2nd messenger than cyclicAMP

• Effective since intracellular concentration is so low, that any absolute change in numbers = a significant change in percentage terms

• Muscle cell contractions, secretion, cell division

11.4 Response

• STP usually leads to a regulation of cellular activities

• Response may occur in the cytoplasm or nucleus

• 2 Types of typical response:1. Enzyme activity is regulated (turned on or off)

2. Synthesis of enzymes is regulated (promoted or inhibited)

Transcription factors

• DNA RNA Protein (Central Dogma)• DNA mRNA = Transcription• mRNA Protein = Translation

• Transcription factors (TF) control which genes are transcribed• Which genes are converted into mRNA • Which genes are turned on or off• Usually TFs affect multiple genes

• Typically, the final molecule in a STP is a transcription factor

Signal Amplification

• 2 Reasons for multistep pathways:1. Signal Amplification

2. Specificity of Cell Signaling

• Signal Amplification• Intermediates in the pathway exist in active form

long enough to activate numerous other molecules before becoming inactive

Signal Specificity

• Different cells have different proteins• Different receptor proteins• Different relay proteins or molecules

• Allows different cells to have a different response to the same signal• In Liver cells: Epinephrine = glycogen breakdown

glucose production• In cardiac muscle: Epinephrine = rapid &

enhanced contractions

Scaffolding Proteins

• Definition - large relay proteins that physically hold several other relay proteins• Physical proximity significantly increases

efficiency of signal transfer• Scaffolding in brain cells hold together networks

of signaling-pathway proteins at synapses

Signal Termination

• Just as certain molecules are activated, they too can be inactivated

• Signal molecule leaves the receptor = inactivation

• Protein phosphatases inactivate phosphorylated protein kinases

• Soon the target cell is returned to its inactive form, and ready to be activated again.