Communication: Cell Signaling

Principles of Cell Signaling

Cell signals is the process of converting
extracellular signals into intracellular
responses.
Key players are:
• Signaling molecules
• Receptors
• Signal transduction proteins
• Second messengers
• Effector proteins
 Signals & Cellular Distance

Endocrine signaling acts over long Paracrine signaling acts over very short
distances within the organism (e.g., distances between neighboring cells
Insulin). (e.g., Neurotransmitters).

Autocrine signaling, cells release signals Signaling systems involving plasma

that act on their own surface receptors membrane-attached proteins act via
direct cell-to-cell contact (Immune
(Growth factors).
reponse).
 Signal Transduction: Kinases/Phosphatases
Two main groups of proteins regulate
intracellular signal transduction:
• Protein kinases:
Kinases use ATP to phosphorylate amino
acid side-chains in target proteins.
Tyrosine or serine/threonine.
• Phosphatases:
Phosphatases hydrolyze phosphates off
of these residues.
Kinases and phosphatases act together
to regulate function of many cellular
protein.
 Kinase mediated Cell Signaling
In the absence of a bound ligand, kinase is
in inactive state to a receptor.
Ligand binding triggers a conformational
change in the receptor leading to kinase
activation.
The kinase phosphorylates inactive form of
a specific transcription factor (TF), leading
to its dimerization.
Activated TF moves into the nucleus and
activates the transcription of target genes.
A phosphatase in nucleus subsequently
removes the phosphate group from the
transcription factor to form inactive
monomers.
 GTPase: A switch
GTPases are active when bound to GTP.
Inactive when bound to GDP.
Guanine nucleotide-exchange factors
(GEFs) promote exchange of GTP for
GDP.
GTPase-activating proteins (GAPs),
stimulate the rate of GTP hydrolysis to
GDP.
It acts as a timer to switch on or off of Trimeric G Protein (Large)
signaling proteins to regulate cell Monomeric G Protein (Small)
function.
 Heterotrimeric G Protein
• Gα subunit with bound GDP is
complexed with Gβγ with empty
receptor.
• Binding of a ligand to a G protein-
coupled receptor changes the
conformation and bind to the Gα
subunit.
• This binding releases the bound GDP.
• Activated ligand-bound receptor acts as
a GEF for Gα subunit and binds GTP.
• Gα with bound GTP dissociate from Gβγ.
• Gα·GTP interacts with and activates an
effector protein.
• Gα -GTP hydrolyse to GDP.
 GPCR: Ion Channels
The neurotransmitter, acetylcholine
(ACH) binds to its receptor.
The binding of ACH to this receptor
triggers dissociation of Gα-GTP from
Gβγ.
Gβγ directly binds to and opens a K+
channel.
K+ moves outside the cell increases the
positive charge outside the
membrane.
Neurotransmitter binding to receptors
causes the ion channel to open or
close, leading to changes in the
membrane potential.
 GPCR: Transcription

• Receptor stimulation leads to activation of

protein kinase A (PKA) through cAMP.
• Catalytic subunits of PKA translocate to the
nucleus.
• Phosphorylate and activate the CREB
transcription factor.
• Phosphorylated CREB associates with the
co-activator and stimulate transcription of
the target genes.
 GPCR & Second Messenger
Second messengers participate in pathways
that are initiated by both G protein-coupled
receptors.
The first messenger activates a G protein-
coupled receptor, which activates a specific G
protein.
In turn, the G protein activates adenylyl
cyclase, which catalyzes the conversion of ATP
to cAMP.
The cAMP then acts as a second messenger
and activates another protein, usually protein
kinase A, leading to cellular responses
Cholera toxin and Diarrhea
 Monomeric G Protein
Epidermal growth factor (EGF) and
many other growth factors receptors
are RTKs.
The cytosolic adapter protein GRB2
and Sos binds to a specific phospho
tyrosine on an activated receptor.
Sos acts as GEF and promotes
formation of active Ras·GTP.
Ras is a monomeric G protein.
Activated Ras is tethered to the
cytosolic surface of the plasma
membrane and triggers cell growth.
LDL Receptor-mediated Endocytosis
Insulin Receptor- Glucose Uptake
 Mannose Receptor: Phagocytosis
Receptor

Many bacteria and other pathogens bears

mannose residues on their surface.

Macrophage express a receptor which

bind mannose residue.

Thus, these pathogens are taken in in the

cells through mannose-receptor mediated
endocytosis.
Apoptosis In extrinsic pathway, the death ligands bind to death
receptors.

The binding of ligand recruits the adaptor proteins

forming death inducing signalling complex (DISC).

Formation of DISC brings procaspase molecules.

Active caspase-8 also mediates the cleavage of

proapoptotoc protein, BID. which subsequently
releases mitochondrial proapoptotic factors.

In case of intrinsic pathway, stress signal causes the

binding of cytoplasmic proteins, BAX and BID to the
outer membrane of mitochondria.

Another mitochondrial protein BAK interacts with BAX

and BID causing release of cytochrome c into the
cytosol.

This binds to Apaf-1 which then forms apotosome that

triggers the activation of procaspase-9.

Activated caspase-9 further initiates the caspase

cascade leading to apoptosis.
Communication: cells of Immune system

Cytotoxic T cells directly interacts

with pathogen infected cells,
secrete mediators and kills
infected cells.

Antigen presenting cells, present

processed antigen on their cell
surface.
This is recognised by T cell
receptor and then interacts with
B cells.
References
1. CAMPBELL B I O L O G Y (9th Edition)
Chapter 11

Jane B. ReeceLisa A.
Urry
Michael L. Cain
Steven A. Wasserman
Peter V. Minorsky
Robert B. Jackson