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Lecture 5

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Signal Transduction

• How are signals transmitted from the outside of


the cell to the inside, allowing cells to modify
their behavior.
– Grow or don’t grow
– Die
– Kill
– Move or don’t move
– Contract
– Turn on or off genes
We’ve seen that the bilayer is a barrier to physical substances… it’s also a
barrier to many kinds of information

Info
How are signals transmitted across the membrane
Hydrophobic signaling molecules can
cross the membrane directly
– Steroid Hormones
• The receptor for this signal is in
the cytoplasm or nucleus
– Nitric Oxide/Carbon Monoxide
• Dissolved gas regulates many
pathways

Hydrophilic signaling molecules cannot


cross the membrane
• They need to indirectly signal across the
membrane by binding to the extracellular
domain of transmembrane receptor
proteins
Types of signals
• Signaling via chemical messengers
– Autocrine, paracrine and
endocrine signaling
• Cell surface receptor binds
a molecule secreted by
itself (autocrine), a nearby
cell (paracrine), or a
distant cell (endocrine).

• Contact-dependent signaling
– Cell surface receptor binds a
signal on the surface of
another cell or to extracellular
matrix.
Basic scheme of signal transduction via membrane receptors

•The same signal can bind


to multiple types of
receptor

•The receptor can be


coupled to multiple types
of transducer

•Second messengers can


provide a high degree of
signal amplification

•The same second


messenger can be
coupled to multiple
effectors
Types of plasma
membrane receptors
• Ligand gated channels
– Signal opens a channel-
(ion pore)
• G-protein coupled receptors
– Signal activates a G-
protein
• Enzyme-linked receptors
– Signal activates the
enzymatic activity of the
receptor (usually a
kinase)
G-protein Coupled Receptor Signaling
• Transmembrane Receptor
– Often 7 membrane spanning helices
– Extracellular domain binds small molecule signal on the outside of the cell
(neurotransmitters, hormones, tastants, odors, light)
– Transmit signal to the cytoplasmic domain which changes conformation as a result
– TM receptor acts as a GEF (Guanine Nucleotide Exchange Factor)
• Heterotrimeric G protein (Guanosine nucleotide binding protein) receives signal
– Three different subunits
– Two are tethered to the membrane by a covalently linked lipid
– Can sense the difference in 3D shape of receptor’s cytoplasmic portion when
extracellular portion is bound vs. unbound. When bound, they interact.
– Transmits signal to effector protein as a result of GTP-GDP exchange.
G-protein Coupled Receptors (GPCRs)

http://www.youtube.com/watch?v=V_0EcUr_txk
A really really simple example: opening of K channels
by acetylcholine
Adenylyl cyclase: a key target of G protein signaling
• Adenylyl cyclase
– G binds to adenylyl cyclase
activating it
– This enzyme makes cAMP from ATP
• cAMP is an important Second
Messenger
– cAMP binds to Protein Kinase A
(PKA) regulatory subunit causing it
to fall off
• The regulatory subunit blocks
the kinase activity
• The regulatory subunit tethers
the complex in the cytoplasm
preventing the NLS from
causing import
– The catalytic subunit of the kinase is
now active and goes to the nucleus
– PKA phosphorylates nuclear
proteins to change gene expression
Signaling via phosphorylation

Serine/Threonine Kinases:
Phosphorylate specific Serine and/or
Threonine residues in target protein.
PKA, PKC etc.

Tyrosine Kinases:
Phosphorylate specific tyrosine residues.
RTKs, Src etc.

Whether phosphorylation turns a target


“on” or “off”, increasing or decreasing its
activity, depends on the site of
phosphorylation and the protein structure
and is experimentally determined.
Adenylyl cyclase: a key target of G protein signaling
• Signal binds a Receptor
• Receptor interacts with transducer,
the G protein,
• G protein interacts with an effector,
Adenylyl Cyclase,
• AC produces a second messenger
cAMP.
• Second messenger interacts with
effector target, PKA,
• Active PKA phophorylates an effector
target, CREB, which results in change
in gene expression.
The multiple points of signal amplification in
cAMP signaling
Different ligands, receptors and G protein complexes allow
integration of input signals to regulate cAMP output
cAMP is a common second messenger in
signaling
Increases in intracellular calcium are another response mediated by GPCRs

(PIP2)

(DAG)
Ca++ release in response to IP3 is a common example of
second messenger signaling
Calmodulin is one of the main transducers
of Ca2+ signals
Enzyme-linked receptors
Signaling through enzyme-linked receptors typically
involves receptor multimerization

Figure 16-15c Essential Cell Biology (© Garland Science 2010)


Receptor Tyrosine Kinases
• Usually single pass
transmembrane proteins
• Bind ligand on the outside of the
cell
• Binding causes the receptor to
dimerize; homo- and hetero-
• Response is the cross-
phosphorylation of part of the
cytoplasmic tail of the receptors
– Phosphorylation is always on
tyrosine so these are called
receptor tyrosine kinases
(RTK)
• The receptor is both a ligand
binding protein and a kinase that
phosphorylates itself!
Transduction is via protein binding to the receptor
• Phosphorylated receptor is recognized by several types of proteins
(SH2 domain containing proteins)
• Binding causes a change in those protein activities, leading to many downstream effects.
• Ex. 1: Activated RTKs can activate phospholipase C and trigger IP3/calcium signaling and
PKC activation (like some GPCRs; see earlier slides).
• Ex. 2: Activated RTKS can activate a phosphorylation cascade that stimulates the nucleus
to cause cells to proliferate via the MAP kinase cascade (next slides).
Signaling through growth factor receptors can activate Mitogen-
Activated Protein Kinases through another family of G proteins

SH2 (GEF)

Figure 16-31 Essential Cell Biology (© Garland Science 2010)


Figure 16-32 Essential Cell Biology (© Garland Science 2010)
Signaling through growth factor receptors can activate
PI3 kinase signaling

Figure 16-33 Essential Cell Biology (© Garland Science 2010)


Signals mediated by GPCRs and RTKs overlap

Figure 16-42 Essential Cell Biology (© Garland Science 2010)


Map Kinase & G-protein Pathways

Do Not Memorize!

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