Cell Biology

Unit 11

No cell can live in isolation, must interact with

environment

In multicellular organisms, cells must communicate with each other

Growth involves intricate signaling

Same with Differentiation

Even Metabolism requires signaling

Signalling molecules

Receptors

Signalling intermediates

Effector proteins

Depending upon distance travelled by signalling molecule

◦ Endocrine

◦ Paracrine

◦ Autocrine

◦ Contact dependent

Earl W. Sutherland, discovered how hormone epinephrine acts on cells, suggested that cells receiving signals went through three processes:

◦ Reception of signal

◦ Transduction of signal

◦ Response to signal

EXTRACELLULAR

FLUID

Reception

Plasma membrane

Transduction CYTOPLASM

Receptor

Signal

molecule

Relay molecules in a signal transduction

pathway

Response

Activation

of cellular

response

Stages in Cell Signaling

Highly specific binding of signaling molecule to its receptor

Binding leads to conformational change in receptor often initiation of signal transduction

Most receptors are plasma membrane proteins

Some receptors present in the cytosol or nucleus

Small or hydrophobic chemical messengers can cross plasma membrane and activate intracellular receptors

e.g. steroid and thyroid hormones

An activated hormone-receptor complex can act as a transcription factor

EXTRACELLULAR

FLUID

Plasma

membrane

The steroid

hormone testosterone

passes through the

plasma membrane.

Testosterone binds

to a receptor protein

in the cytoplasm,

activating it.

The hormone-

receptor complex

enters the nucleus

and binds to specific

genes.

The bound protein

stimulates the

transcription of

the gene into mRNA.

The mRNA is

translated into a

specific protein. CYTOPLASM

NUCLEUS

DNA

Hormone

(testosterone)

Receptor

protein

Hormone-

receptor

complex

mRNA

New protein

Intracellular Receptors

Water-soluble signaling molecules bind to receptor proteins present in plasma membrane

Three main types of membrane receptors:

◦ G-protein-linked receptors

◦ Enzyme coupled cell surface receptors

◦ Ion channel receptors

Plasma membrane receptor

G-protein acts as an on/off switch

GDP bound to G protein is inactive

G-protein-linked receptor

Receptor tyrosine kinases (RTKs)

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

Transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates – signaling intermediates

Signal

molecule

a Helix in the

membrane

Signal-binding site

Tyr

Tyr

Tyr Tyr

Tyr

Tyr Tyrosines

Receptor tyrosine

kinase proteins

(inactive monomers) CYTOPLASM

Tyr

Tyr

Tyr Tyr

Tyr

Tyr Tyr

Tyr

Tyr Tyr

Tyr

Tyr

Tyr

Tyr

Tyr Tyr

Tyr

Tyr

Activated tyrosine-

kinase regions

(unphosphorylated

dimer)

Signal

molecule

Dimer

Fully activated receptor

tyrosine-kinase

(phosphorylated

dimer)

Tyr

Tyr

Tyr Tyr

Tyr

Tyr P

P

P

P

P

P ATP 6 ADP

Tyr

Tyr

Tyr Tyr

Tyr

Tyr P

P

P

P

P

P

Inactive

relay proteins

Cellular

response 2

Cellular

response 1

Activated relay

proteins

6

An ion channel receptor acts as a gated channel

Upon binding signal molecule allows specific ions, such as Na+ or Ca2+, to pass through a receptor channel

Signal molecule (ligand)

Gate closed Ions

Ligand-gated ion channel receptor

Plasma membrane

Gate closed

Gate open

Cellular response

May involve multiple steps

Helps in amplification & Transmission of a signal

Provides more opportunities for coordination and regulation

Molecules that relay a signal from receptor to response are mostly proteins

Extracellular signal molecule that binds to membrane receptor - First messenger

Second messengers are small, non-protein, water

soluble molecules or ions

Second messengers can readily spread in cell by diffusion

Second messengers propagate pathways initiated by G protein-linked receptors and receptor tyrosine kinases

Most widely used second messengers

Discovered by Earl W. Sutherland Jr.

Formed from ATP by Adenylyl Cyclase, in response to an extracellular signal

Many signal molecules trigger formation of cAMP

cAMP usually activates Protein Kinase A, which phosphorylates various other downstream proteins

cAMP

ATP Second

messenger

First messenger

(signal molecule

such as epinephrine)

G-protein-linked

receptor

G protein

Adenylyl

cyclase

Protein

kinase A

Cellular responses

GTP

Ca2+ is an important second messenger

Cells tightly regulate Ca2+ concentration

A signal may trigger an increase in Ca2+ in cytosol

Pathways leading to the release of Ca2+ involve inositol

triphosphate (IP3) and diacylglycerol (DAG) as

second messengers

CYTOSOL

Ca2+ Endoplasmic reticulum (ER)

IP3-gated

calcium channel

IP3 (second

messenger)

DAG

PIP2 G-protein-linked

receptor Phospholipase C

G protein

Signal molecule

(first messenger)

EXTRACELLULAR

FLUID

GTP

Ca2+

(second

messenger)

Various

proteins

activated

Cellular

re-

sponses

Multi-step signaling pathways have important

benefits:

◦ Amplification of the signal

◦ Contributing to the specificity of the response

◦ Provide many opportunity to regulate the signaling cascade

Binding of epinephrine to G-protein-linked receptor (1 molecule)

Reception

Transduction

Inactive G protein

Active G protein (102 molecules)

Inactive adenylyl cyclase

Active adenylyl cyclase (102)

ATP

Cyclic AMP (104)

Inactive protein kinase A

Inactive phosphorylase kinase

Active protein kinase A (104)

Active phosphorylase kinase (105)

Active glycogen phosphorylase (106)

Inactive glycogen phosphorylase

Glycogen

Response

Glucose-1-phosphate

(108 molecules)

Amplification of the signal

Different cell types have different set of proteins

Different protein profile gives each cell type

specificity in detecting and responding to signals

Response of a cell to a signal depends on cell’s

protein set

Pathway branching and “cross-talk” further help

the cells to coordinate and regulate response to

incoming signals

Signal

molecule

Receptor

Relay

molecules

Response 1 Response 2 Response 3

Cell B. Pathway branches, leading to two responses

Cell A. Pathway leads to a single response

The Specificity of Cell Signaling

Cell C. Cross-talk occurs between two pathways

Response 4 Response 5

Activation

or inhibition

Cell D. Different receptor leads to a different response

Termination mechanisms are an essential aspect of cell signaling

A way of regulation and control of cell signaling

When signal molecules leave the receptor, the receptor reverts to its inactive state

Signal may terminate by dephosphorylation of signaling intermediates (relay proteins)

Regulation of Flagella movement by histidine kinase – a good example of prokaryote signaling

Also an evidence of evolution of Signaling mechanism from prokaryote to eukaryote

Clock wise and anticlockwise movement of flagella regulated by signaling- determines its swimming pattern

Cell signalling is basis of Prokaryote and Eukaryote life

For normal functioning coordination of every signaling

pathway is necessary

Altered signalling pathways may lead to diseases

Defect can be in any component of signalling ultimately

leading to the disease development

Cell signalling has been identified in Cancer,

Cardiovascular diseases, Alzheimer's disease, and many

other disorders

Cell Signalling – an important area of research for drug

discovery

Cell signaling - essential for survival of both uni-

and multi- cellular organisms

Involves various components and steps

Smooth progression and tight control is required

for homeostasis

Many diseases result from defects in cell signaling

THE END