A Simple Intracellular Signaling Pathway Activated

by an Extracellular Signal Molecule

Figure 15-1. Molecular Biology of the Cell 6e (Garland Science, 2015).

Characteristics of Extracellular Signaling Molecules

Secreted from a signaling cell
Peptides, amino acids nucleotides steroids retinoids, fatty acid derivatives,
dissolved gases
Released into extracellular space by exocytosis or diffusion

Characteristics of Receptor Proteins

Target cell responds by means of a receptor
Receptors are usually on the surface of the target cell (but can be found
inside the cell)
Often a transmembrane protein
Binds extracellular signal molecule with high affinity
Upon binding the signaling molecule (ligand), the receptor *activates* a series of
intracellular signals that alters cell behavior.
2

Forms of Intercellular Signaling

Extracellular signal molecules can act over either short or long distances
Signaling and target cells are usually distinct cell types
Figure 15-2. Molecular Biology of the Cell 6e ( Garland Science, 2015).

The Binding of Extracellular Signal Molecules to Either

Cell-Surface or Intracellular Receptors

(water soluble)
(Diffuses through lipid bilayer)

Most signal molecules are hydrophilic and unable to cross the plasma membrane of the target
cell. They bind to cell surface receptors, which generate intracellular signals within the target.

Figure 15-3. Molecular Biology of the Cell 6e ( Garland Science, 2015).

Cells Depend on Multiple Extracellular Signals

programmed
cell death

Specific combinations of signaling molecules can regulate cell behavior

Figure 15-4. Molecular Biology of the Cell 6e ( Garland Science, 2015).

Various Responses Induced by the Neurotransmitter Acetylcholine

A

Signal molecules differentially affect distinct target cells. The effect of a signal molecule on a cell
is regulated by the intracellular molecules which respond to the receptor, downstream effector
proteins and genes activated. These are dictated by the cells predetermined state which
depends on the cells developmental history.

Figure 15-5. Molecular Biology of the Cell 6e (Garland Science, 2015).

Three Classes of Cell-Surface Receptors

A) Ion Channel-Coupled Receptors

Protein lined channel

through the membrane
receptor = channel protein

B) G-Protein-Coupled Receptors

Receptor is a 7 pass
transmembrane protein
which activates a
membrane bound
(usually trimeric)
GTPase (G-protein)
C) Enzyme-Coupled Receptors

Single pass receptor is an

enzyme or binds directly to
an enzyme

Figure 15-6. Molecular Biology of the Cell 6e (Garland Science, 2015).

Cell Surface Receptors Relay Signals Via Intracellular

Signaling Molecules

Two Types of Intracellular Signaling Proteins

That Act as Molecular Switches

GTPase
Intrinsic
GTPase
activity

Kinase
(ser/thr

phosphatase

or tyr)

-proteins activated or inactivated

by phosphorylation

Figure 15-7. Molecular Biology of the Cell 6e (Garland Science, 2015).

-activated by GTP
-monomeric trimeric

Three Types of Intracellular Signaling Complexes

A

Scaffold proteins
serve as a strategy for enhancing
specificity of interactions between
signaling molecules by localizing them.

organize groups of interacting signaling

proteins into signaling complexes
ensure they interact with each other and not
with inappropriate partners.
increase local concentrations
speed
efficiency

decreases cross talk with other signaling

pathways

9
Figure 15-10. Molecular Biology of the Cell 6e (Garland Science, 2015).

Modular interaction domains mediate interactions

between intracellular signaling proteins

activated
insulin
receptor

(insulin receptor substrate)

-small interaction domains found in many signaling proteins
-bind structural motifs found in other proteins and lipids
Figure 15-11. Molecular Biology of the Cell 6e (Garland Science, 2015).

10

Molecular Interaction Domains Allow

Assembly of Signal Complex
PTB

Phosphotyrosine binding

SH2

Src homology 2 binds phosphorylated tyrosine

within a particular peptide sequence

SH3

PH

Pleckstrin Homology - binds phosphoinositides to

enable membrane docking

Adaptor
Protein

link proteins together through 2 or more interaction

domains

Chains or Branching
Networks

signaling molecules assemble into complexes to

form chains and branching networks which cluster
in the lipid bilayer (rafts) of plasma membrane

Src homology 3 binds proline-rich sequences

11

Some Ways in Which Target Cells Can Become Adapted

(Desensitized) to an Extracellular Signal Molecule

internalization

internalization &

in appropriate phosphorylation

degradation

Adaptation of target cells to high levels of signaling proteins

Adjust sensitivity to signal

Figure 15-20. Molecular Biology of the Cell 6e (Garland Science, 2015).

12

Signaling through G-protein Coupled Receptors

Activation of a G protein by an activated GPCR

GPCRs
large family of
receptors which mediate
cellular responses to
extracellular signals

ligand bound GPCR binds to and

activates G-protein by triggering the
exchange of GDP for GTP

-signal polypeptide chain

which passes through
the membrane 7 times

-GTP bound G-protein activates

effector proteins such as the
membrane-bound enzyme adenylate
cyclase

-function through Gproteins to transmit

signals
-half of all known drugs
work through GPCRs or
their signaling pathways

Figure 15-23. Molecular Biology of the Cell 6e (Garland Science, 2015).

Adenylate cyclase

Cyclic AMP
(cAMP)

GPCRs linked to a stimulatory Gprotein (Gs) activate adenylate

cyclase inhibitory G-protein (Gi)
inhibit adenylate cyclase

13

The Synthesis and Degradation of Cyclic AMP

cAMP functions as a second

messenger to activate cAMPdependent enzymes in the cytosol,
mainly cAMP dependent protein
kinase A (PKA).
PKA phosphoroylates ser-thr
residues on target proteins

Figure 15-25. Molecular Biology of the Cell 6e (Garland Science, 2015).

14

The Activation of Cyclic-AMP-Dependent Protein Kinase (PKA)

controls activity
and subcellular
localization

Figure 15-26. Molecular Biology of the Cell 6e (Garland Science, 2015).

15

How a Rise in Intracellular Cyclic

AMP Concentration Can Alter Gene
Transcription

Figure 15-27. Molecular Biology of the Cell 6e (Garland Science, 2015).

16

Some Hormone-Induced Cell Responses Mediated by Cyclic AMP

Table 15-1. Molecular Biology of the Cell 6e (Garland Science, 2015).

17

G-protein Signaling Through Phospholipids

The Hydrolysis of PI(4,5) P2 by Phospholipase C-

(DAG)

Figure 15-28. Molecular Biology of the Cell 6e ( Garland Science, 2015).

DAG and Ca2+

are considered
second
messengers

18

How GPCRs Increase Cytosolic Ca2+ and Activate Protein Kinase C

Ca2+ is an effective signaling mediator

because its cytosolic concentration is
low (10-7M), whereas extracellular and
lumen concentrations are high (103M).
Ca2+ pumps in plasma and ER
membranes drive Ca2+ out of the cell
into the ER to lower cytosolic
concentrations and terminate Ca2+
signaling.
Figure 15-29. Molecular Biology of the Cell 6e (Garland Science, 2015).

19

The Structure of Ca2+/Calmodulin

Calmodulin is a Ca2+ binding protein which
binds to and activates enzymes. Serves as a
Ca2+ dependent regulatory subunit in many
enzyme complexes. This family of enzymes is
Ca2+/calmodulin-dependent kinases (CaMkinases). They phosphorylate a variety of target
proteins.

Figure 15-33. Molecular Biology of the Cell 6e (Garland Science, 2015).

20

Some Cell Responses in Which GPCRs Activate PLC

Table 15-2. Molecular Biology of the Cell 6e (Garland Science, 2015).

21