Cell signaling involves both long- and short-range signals that can induce different responses in different cell types. Signals are received by receptors on the cell surface or inside the cell and are transmitted through intracellular signaling proteins like kinases and G proteins. This leads to changes in second messengers like cAMP that activate downstream responses. Common pathways involve G protein-coupled receptors activating second messengers or receptor tyrosine kinases activating the Ras pathway to control processes like cell growth, survival, and death.

1. Cell Signaling &
Signal Transduction
By,
Dr. Huma Jawed
Ph.D, Pharmacology

3. Signals can act over long or short range.

4. Long Range Acting
fight or flight response
neurotransmitter
hormone normal function also
stress

5. Short Range Acting
shortest

6. The same signal can
induce different responses
in different cells.
ion channel
receptor
non-ion
channel
receptor

7. Cells integrate multiple signals to
induce a specific response.

8. Responses can be fast or slow, depending on
whether transcription and translation are required.

9. Signals are received by receptors, which can
act on the cell surface or intracellularly.
membrane-permeable
not membrane-
permeable

10. Steroid hormones are
hydrophobic enough
to cross a plasma
membrane and bind
cytosolic nuclear
receptors.

11. Steroid hormones are derived from cholesterol.

12. Blood vessel dilation involves
both membrane permeable and
non-permeable signals.
-Acetylcholine (non-permeable signal)
induces production of diffusible signal
(NO gas) from endothelial cells
-NO gas (permeable signal) induces
production of cGMP second messenger
in smooth muscle cells
Acetylcholine: NO:
non-permeable permeable
Nitric Oxide

13. Cell-surface receptors relay the signal through
intracellular signaling molecules to final targets.
signal transduced
through chain reaction
of signal molecules
leading to final response Examples: kinases and G proteins

14. Common intracellular signaling proteins
Kinases G proteins
It must be possible for these to return to
ground state, so they can receive future signals.

15. Phosphatases return protein kinases
and their targets to ground state.
sometimes
dephosphorylation
turns protein ON

16. GTP hydrolysis returns G proteins to ground state.

17. Monomeric G proteins are
assisted by GEFs and GAPs
activates
inactivates
Guanine nucleotide
Exchange Factor
GTPase-Activating
Protein

18. Three Classes of
Membrane-Bound
Receptors

19. Ion-Channel-Coupled Receptors
Responsible for depolarizing
post-synaptic membranes to threshold
fast and short range

20. GPCR
G Protein-Coupled Receptor
Can Achieve Astonishing Speed and Sensitivity
largest family of cell surface receptor; > 800 types in humans
response to acetylcholine in cardiac pacemaker cells

21. Enzyme-Coupled Receptors
Responses typically slow, but highly sensitive.
Often a Kinase

22. GPCR
-contain seven
transmembrane α-helix
domains
-signal binding induces
conformational change
by shifting positions of
transmembrane domains
-activates G protein

23. Conformational change activates G protein complex
active G protein
switches effector
to “on” state

24. G protein switches itself off through GTP hydrolysis
What would
happen if
GTP-hydrolysis
activity mutated?
Locked in
Active State

25. Many Gα subunits activate enzymes
to produce 2nd messenger molecules

27. G-Protein Couples Effector
Enzymes
• Adenylate cyclase (Gαs, Gαi )
• Phospholipase C (Gq)

30.  synthesized from ATP by
adenylyl cyclase enzyme
 destroyed by hydrolysis
to AMP by cyclic AMP
phosphodiesterase enzyme
cAMP is a common second messenger

31. GPCR and cAMP in Glycogen Breakdown
Gαs
“fight or flight” response
of skeletal muscle

32. Activated G protein complex directly stimulates
K+ channel opening in heart pacemaker cells
K+ flow out
hyperpolarizes
cell membrane,
making harder
to activate
βγ

34. Enzyme-Coupled Receptors
Responses typically slow, but highly sensitive.

35. Many Enzyme-Coupled Receptors are
Receptor Tyrosine Kinases (RTKs)
auto-phosphorylation
through phosphorylation

36. Most RTKs activate the
monomeric G protein, Ras
cellular response
often cell growth
& proliferation
Ras is a family of related proteins which is expressed in
all animal cells & organs. All Ras protein family members
belong to a class of protein called small GTPase,

37. When Ras is 'switched on' by incoming signals, it subsequently
switches on other proteins, which ultimately turn on genes
involved in cell growth, differentiation and survival.
Mutations in ras genes may lead to the production of permanently
activated Ras proteins.
As a result, this can cause unintended and overactive signaling
inside the cell, even in the absence of incoming signals.
Because these signals result in cell growth and division, overactive
Ras signaling can ultimately lead to cancer.

38. Survival and growth signals
induce membrane localization of kinases
lipid phosphorylation
Insulin is survival/growth signal
Protein kinase B (PKB), also known as Akt, is a serine/threonine-
specific protein kinase that plays a key role in multiple cellular processes
such as glucose metabolism, apoptosis, cell proliferation, transcription
Akt named after A tumors k mice
with thymus
where it was discovered

39. Activated Akt inactivates pro-apoptotic Bad
and activates anti-apoptotic Bcl2
The Bcl-2-associated death
promoter (BAD) protein
Bcl-2 (B-cell lymphoma 2), encoded in
humans by the BCL2 gene, is the founding
member of the Bcl-2 family of regulator
proteins that regulate cell death

41. Apoptosis
• Apoptosis, or programmed cell death, is a form of cell death that is generally
triggered by normal, healthy processes in the body.
• Necrosis is the premature death of cells and living tissue

42. Intrinsic signals can also induce apoptosis
in response to DNA damage.
IAP (inhibitor of apoptosis)
Bad sequesters Bcl2
to allow Bax channel
formation (pro-apoptotic)
Bax
Apaf-1
Bcl2 sequesters Bax to prevent
Bax channel formation
(anti-apoptotic)
inhibitor
of IAP

43. Fas Ligand (FasL), Fas-associated death domain protein (FADD), death-inducing signalling complex (DISC) domain death
agonist (BID), truncated BID (tBID), B-cell lymphoma 2 (BCL-2), BCL-2 associated x protein (BAX), BCL-2 antagonist killer
1 (BAK1) Pro-apoptotic mitochondrial factors, including DIABLO (direct inhibitor of apoptosis protein-binding protein
with low pI; also known as SMAC), inhibitor of apoptosis proteins (IAPs). Granzyme B can also cleave BID, resulting in
granzyme tBID, which can activate the intrinsic apoptotic pathway. cFLIP (cellular FLIP/caspase 8 inhibitor protein)

44. ICAD= Inhibitors of Caspase-activated DNase

46. Cells integrate multiple signals
into complex responses.