BIOL 130 MIDTERM II

CHANYOUNG KIM

UNIT 8: Cell Communication

Why Cells Communicate
Single celled organisms for the purpose of Social Life
Yeast Mating
Multicellular organisms coordination of
Development (multiplying from single cell)
Growth
o Coordinating whole body growth and development with environment
Day to day physiology
Cell-cell communication is critical in multicellular organism
Long vs Short Range Communication Animal Cells
Hormones produced
in endocrine glands
secreted into
bloodstream and
distributed widely
through out the
body

Paracrine signals
released by cells into
extracellular fluid in
neighbourhood and
act locally

Neuronal signals
transmitted along
axons to remote
target cells

cell-surface-bound
signal molecule
binds to
a receptor protein
on an adjacent cell

Signaling Pathways
Signaling molecule synthesized and released by signalling cell
Signal molecule ravels to target cell
Find receptor protein, protein changes shape, signal transduced
Signal binds to receptor protein on/in target cell
Signal transduction
Change in protein activity (activation/inactivation), changes in gene expression
Changes in cell shape, movement, metabolism, secretion
The same signal can cause different responses, depending on target cell

BIOL 130 MIDTERM II

CHANYOUNG KIM

All cells response can be fast or slow

The Location of the receptor can (usually) be predicted by the chemistry of the signal molecule

Small hydrophobic signal molecules typically enter the cell and regulate gene transcription

BIOL 130 MIDTERM II

CHANYOUNG KIM

Steroid Hormone Mechanism of Action

Steroids are evolutionarily related
Their receptors are member
of nuclear receptor family
of transcription factors

Most signals bind to receptors on plasma membrane

Intracellular Signaling Cascade

Second messenger
Small (non-protein) molecule that relay signals from
cell surface receptors to target molecules within cell

BIOL 130 MIDTERM II

CHANYOUNG KIM

Intracellular Signal Molecules often act as molecular switches

Regulation of Proteins by Phosphorylation

Turning off a signal is just as important as turning it on (faulty on/off switch result in disasters)
Each activation step in a cascade needs to be inactivated
Activity of a protein regulated by phosphorylation depends on balance between activities of its
kinases and phosphates
Many proteins regulate by phosphorylation are themselves kinases phosphorylation cascades
Phosphorylation of proteins is not random
Nothing rand about enzyme catalyzed reaction
Serine / threonine kinases
o Phosphorylate hydroxyl groups of serine and threonine in particular sequences
Tyrosine kinases
o Phosphorylate hydroxyl groups of tyrosine
Serine, threonine, tyrosine, only ones with hydroxyl groups

BIOL 130 MIDTERM II

CHANYOUNG KIM

GTP-Binding proteins (G Proteins)

switch from active to inactive state depending on whether they are bound to GTP or GDP
Once bound to GTP, G protein have intrinsic GTPase activity, turn themselves off by hydrolyzing GTP to GDP
Dissociation of GDP and replacement with a fresh GTP is often in response to a signal
Active form will activate downstream steps in cascade

Overview of Classes of Cell-Surface Receptors 1

Ion channel-coupled receptors (cell surface receptors can itself be an ion channel)

Binding of ligand opens (or closes) ion channel

Flow of ions (inward or outward) changes voltage across membrane
aka neurotransmitter-gated channels ligand-gated channels

Overview of Classes of Cell-Surface Receptors 2

G Protein-coupled receptors (GPCRs)

Binding of ligand activates trimeric GTP-binding proteins (G-Proteins), which in turn activate an enzyme or
ion channel in membrane to set off cascades
About half of know drugs act via GPCR

Overview of Classes of Cell-Surface Receptors 3

Enzyme-coupled receptors

Receptors are enzymes themselves or associated with enzymes

BIOL 130 MIDTERM II

CHANYOUNG KIM

Activation of a G-Protein Coupled Receptors (GPCR)

How long does a G-Protein signal last?

As long as the alpha and beta/gamma subunits are free
Which is as long as the G-subunit is bound to GTP
Normally G hydrolyzes GTP GDP within a few seconds and re-associates with -subunits
What are the consequences of disruption in G function?
Cholera bacterium produces toxin that enters intestinal cells and alters G subunit
Interferes with GTPase activity inability to turnoff
Cell is continuously active prolonged secretion into gut
o Life threating diarrhea, dehydration
Whooping cough bacterium colonizes lung, produces pertussis toxin that enter cells and alters G subunit
(off switch)
Prolonged, inappropriate signal that generates coughing

BIOL 130 MIDTERM II

CHANYOUNG KIM

What are the downstream targets of G-Protein Cells?

Ion channels (K+ channels in heart muscle cells)

Many GPCRs activate adenylyl cyclase

Membrane-bound enzyme that catalyzes

synthesis of 2nd messengers

BIOL 130 MIDTERM II

CHANYOUNG KIM

Epinephrine acts via a GPCR that activates adenylyl cyclase

Epinephrine = adrenalin (signal) fight or flight reaction

Adrenaline activates GPCR

Changes shape of alpha dump ADP
Alpha subunit binds to ATP
Activates target protein (adenylyl cyclase)
Catalyzes synthesis of cyclic AMP (2nd
messenger)
Cyclic AMP changes shape of inactive downstream
protein kinases A (PKA)
Active PKA
Transfer phosphate group from ATP ( ADP)
onto inactive phosphorylase kinase ( active)
Active PK transfers phosphate group onto another target
protein
Breaks glycogen down to glucose

Cyclic AMP signalling also activate gene transcription

Genes regulated via cAMP cascades will have upstream cAMP response elements (sequences) recognized
by these transcription factors

Adrenaline activates GPCR

Changes shape of alpha dump ADP
Alpha subunit binds to ATP
Activates target protein (adenylyl cyclase)
Catalyzes synthesis of cyclic AMP (2nd
messenger)
Cyclic AMP changes shape of inactive downstream
protein kinases A (PKA)
Active PKA
Escorted through nuclear pore
Activate Phosphorylase (transfer phosphate
group) regulation of transcription factor
Recognize upstream regulatory protein

BIOL 130 MIDTERM II

CHANYOUNG KIM

Other Cell responses mediate by GPCRs and cyclic AMP

ACTH = adrenocorticotropic hormone

TSH = thyroid stimulating hormone
FSH = follicle stimulating hormone
LH = luteinizing hormone

Many GPCRs activate phospholipase C.

Beta/gamma complex activates phospholipase C

Breakdown phospholipid
Inositol phospholipid breaks down diacylglycerol binds to PKC (phosphorylate target protein)
Inositol 1,4,5-triphosphate (IP3 free in cytosol) binds to Ca2+ channel
o Allow pass of Ca2+ down gradient
o High concentration in ER, low in cytosol
Ca2+ binds to PKA activated

BIOL 130 MIDTERM II

CHANYOUNG KIM

Ca2+ as an Intracellular Signal

Concertation in the cytosol are very low compared to outside the cell (1,000-fold difference steep
concentration gradient)
Can be at very high concentration within storage organelles
o E.g. endoplasmic reticulum
Cytosolic [Ca2+] can be rapidly increased
By opening of channels on plasma membrane
By opening of channels on ER
o Leading to a rapid signal
Binding of Ca2+ activates many different proteins
Activation of Calmodulin (CaM) by Ca2+

Cellular Responses to IP3-stimulated Ca2+ release

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BIOL 130 MIDTERM II

CHANYOUNG KIM

Overview of Classes of Cell-Surface Receptors 3

Enzyme coupled receptors

Receptors are enzymes themselves or associated with enzymes

Activation of Receptor Tyrosine Kinase (RTK)

RTKs are largest class of enzyme-coupled receptors. (Kinase mediating GPCR responses PKA, PKC are
ser/thr kinases)
Signal proteins recruited to cytosolic tails of RTKs activate other downstream signals

All RTKs activate the monomeric GTP-binding protein Ras

Ras

Small, monomeric G-protein bound to inner membrane by lipid tail

Similar to G-subunit of trimeric G-proteins
o Molecular switch
Active when bound to GTP, turns it self off by hydrolyzing it to GDP
o sets off relay signals

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BIOL 130 MIDTERM II

CHANYOUNG KIM

RTKs, Ras and Cancer

Ras is one member of large family of small G-proteins involved in signal transduction
Mediates many pathways involved in cell growth, differentiation and survival
Mutations in Ras can lead to permanently activated proteins
o Signaling inside cell even without incoming signals
Uncontrolled growth/division cancer

Ras is the most commonly mutated gene in human cancer cells

Mutations that permanently activate Ras found in one third of all cancer (90% in certain types of
cancer)
Mutations of other components of RTK/Ras pathway in many other cancers

Cell Integrates signals from many pathways

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