The document discusses various forms of cell signaling, including autocrine, paracrine, endocrine, and juxtacrine signaling. It also describes the main stages of cell signaling: reception, transduction, and response. Several key cell signaling pathways are explained in detail, such as G-protein coupled receptor signaling and cyclic AMP signaling. Receptor tyrosine kinase signaling is also summarized. The document provides an overview of the complex system of cell signaling and communication between cells.

1. Presented by: Dr. Arpita Sain
Cell Signaling

2. Introduction
Complex system of communication
Cellular activities
Cell functions are coordinated
Use both unicellular and multicellular
organism
Mediate by extracellular molecule

3. Forms of Signaling
• Autocrine
Paracrine Endocrine Juxtacrine
Depending upon distance travelled by signaling
molecule it divide into four categories:
i. Autocrine
ii. Paracrine
iii. Endocrine
iv. Juxtacrine

4. Stage of Cell Signaling
Reception Transduction Response
Extracellular
fluid
Cytoplasm
Relay molecule
Signaling
molecule
Plasma membrane
Activation
of cellular
response

5. Cell Signal Transduction
Pathways

6.  Signal transduction is the process by which a chemical or physical signal is transmitted
through a cell as a series of molecular events most commonly protein phosphorylation
catalysed by protein kinase, which ultimately results in a cellular response.
 Any process occurring within cells that convert one kind of signal stimulus into
another type
 It also known as cell signaling in which the transmission of molecular signals from a
cell's exterior to its interior.
 .This step is initiated by cell-surface receptors which triggers a biochemical chain of
events inside the cell creating a response.
SIGNAL TRANSDUCTION

7. SIGNALING THROUGH G-PROTEIN-COUPLED
RECEPTORS
Synonym: 7-TM
Serpentine receptors
Heptahelical receptors
GPLR
 Posses seven membrane spanning domains or transmembrane
helices

8. Structure of G- protein
 G proteins, also known as guanine nucleotide
binding proteins, involved in transmitting signals
and function as molecular switches.
 Heterotrimeric protein
 G protein complexes are made up of
• alpha (α)
• beta (β)
• gamma (γ) subunits
α subunit
γ subunit

9. Activation
 Binding of an extracellular signal molecule to a
GPCR changes the conformation of the receptor
 The AH domain of the G protein α subunit moves
outward to open the nucleotide-binding site,
thereby promoting dissociation of GDP.
 GTP binding then promotes closure of the
nucleotide-binding site and causes dissociation of α
subunit .

10. • Cyclic AMP is synthesized
from ATP by an enzyme
called adenylyl cyclase
• Adenylyl cyclase is a large,
multipass transmembrane
protein with its catalytic
domain on the cytosolic side
G Proteins Regulate the
Production of Cyclic AMP

11. Cyclic-AMP-Dependent Protein Kinase (PKA) Pathway
 The binding of cAMP to the regulatory
subunits of the PKA tetramer induces a
conformational change, causing these
subunits to dissociate from the catalytic
subunits, thereby activating the kinase
activity of the catalytic subunits.
 once the catalytic subunits are freed and
active, they can migrate into the nucleus

12.  The binding of signal activates adenylyl cyclase via
Gs and thereby increases cAMP concentration in the
cytosol.
 This rise activates PKA, and the released catalytic
subunits of PKA can then enter the nucleus, where
they phosphorylate the transcription regulatory
protein CREB.
 Once phosphorylated, CREB recruits the coactivator
CBP, which stimulates gene transcription.

13. G Proteins Signal Via Phospholipids
(Inositol Phospoloipid signaling pathway)

14.  The activated GPCR stimulates the plasma-membrane-bound phospholipase C-β
(PLCβ) via a G protein called Gq.
 Two second messengers are produced when PI(4,5)P2 is hydrolyzed by activated
PLCβ.
 Inositol 1,4,5-trisphosphate (IP3) diffuses through the cytosol and releases Ca2+
from the ER by binding to and opening IP3-gated Ca2+-release channels (IP3
receptors) in the ER membrane.
 Diacylglycerol remains in the plasma membrane and, together with Ca2+, helps
to activate protein kinase C (PKC), which is recruited from the cytosol to the
cytosolic face of the plasma membrane

15. Signaling Through Enzyme-coupled
Receptors

16. There are various classes of enzyme-coupled receptors, the most
common of which are
• Receptor tyrosine kinases (RTKs).
• Tyrosine-kinase-associated receptors.
• Receptor serine/threonine kinases.

17. The binding of ligand on the extracellular side causes the receptors to dimerize and receptor activates the tyrosine
kinase domain on the cytosolic side.
This leads to phosphorylation of tyrosine side chains on the cytosolic part of the receptor, creating phosphotyrosine
docking sites for various intracellular signaling proteins that relay the signal.
Receptor Tyrosine Kinases (RTKs)

18. • EGF binding results in a conformational change that
promotes dimerization
• Instead, dimerization orients the internal kinase domains
into an asymmetric dimer, in which one kinase domain
(the “activator”) pushes against the other kinase domain
(the “receiver”), causing an activating conformational
change in the receiver.
• The active receiver domain then phosphorylates multiple
tyrosines in the C-terminal tails of both receptors,
generating docking sites.

19. JAK–STAT Signaling Pathway (Tyrosine-kinase-associated receptors)
• The large family of cytokine receptors includes receptors for many kinds of
local mediators, as well as receptors for some hormones, such as growth
hormone and prolactin.
• These receptors are associated with cytoplasmic tyrosine kinases called Janus
kinases (JAKs), which phosphorylate and activate transcription regulators
called STATs (signal transducers and activators of transcription).

20. The binding causes two separate receptor
polypeptide chains to dimerize.
The associated JAKs phosphorylate each
other on tyrosines to become fully activated.
After which they phosphorylate the
receptors to generate binding sites for the
SH2 domains of STAT proteins.
The JAKs also phosphorylate the STAT
proteins, which dissociate from the receptor
to form dimers and enter the nucleus to
control gene expression.

21. The TGFβ dimer promotes the assembly of a tetrameric
receptor complex containing two copies each of the type-I
and type-II receptors.
The type-II receptors phosphorylate specific sites on the
type-I receptors, thereby activating their kinase domains and
leading to phosphorylation of Smads
Smads open up to expose a dimerization surface when they
are phosphorylated, forming trimeric Smad complex.
The phosphorylatedSmad complex enters the nucelus
Smad-dependent signaling pathway

29. Reference
http://en.wikipedia.org/wiki/Cell_signaling
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellSignaling.html
Congreve M, Marshall F (March 2010). "The impact of GPCR structures on
• pharmacology and structure-based drug design". Br. J. Pharmacol. 159 (5): 986–
96.
http://www.britannica.com/science/ion-channel
Rang & Dale's Pharmacology

30. Thank You