The document discusses 10 major classes of receptors involved in signal transduction: 1. Receptor tyrosine kinases activate upon ligand binding and dimerization, phosphorylating substrates. 2. Serine-threonine kinase receptors like TGF-β receptors form complexes upon ligand binding and cross-phosphorylate. 3. Receptor phosphotyrosine phosphatases regulate signaling pathways and are inhibited by dimerization. 4. G protein-coupled receptors signal through heterotrimeric G proteins upon agonist-induced conformational change. 5. The Notch receptor is cleaved upon ligand binding, releasing a transcriptional regulator.

1. LAB EVALUATION OF
CELL DISORDERS
3) Receptors
Ola H. Elgaddar
MD, PhD, CPHQ, LSSGB
Lecturer of Chemical Pathology
Medical Research Institute
Alexandria University
Ola.elgaddar@alexu.edu.eg

2. Signal Transduction Systems:
-Signal transduction is the chemistry that
allows communication at the cellular level.
- Cells sense signals from the extracellular
and intracellular environments, as well as
directly from other cells.

3. - Cells respond to these signals in a variety
of ways, primarily by modifying protein
levels, activities, and location.
- Protein levels are controlled by rates of
transcription, translation, and proteolysis,
whereas protein activities are affected by
covalent modifications and non-covalent
interactions with other proteins and small
molecules.

4. - Most signals are initiated by ligands and are
sensed by the receptors to which they bind.
- Binding of a ligand to a receptor stimulates the
activities of proteins necessary to continue the
transmission of the signal through the formation of
multi-protein complexes and the generation of
small-molecule second messengers.
- Integration of signals from multiple pathways
determines the cell's ultimate response to
competing and complementary signals.

5. Signals (Ligands):
-Signal transduction pathways
respond to different types of stimuli.
- Molecules that initiate signaling
cascades include proteins, amino
acids, lipids, nucleotides, gases, and
light.

6. Several classifications for signals!
- Some signals are continuous, such as
those sent by the extracellular matrix,
whereas others are episodic, like the
secretion of insulin by pancreatic cells
in response to increases in blood
glucose.

7. - Signaling molecules originate from a
variety of sources. Some, such as
neurotransmitters, are stored in the
cell and are released to provide
communication with other cells under
specific conditions. Other ligands are
stored outside the cell (e.g., in the
extracellular matrix) and become
accessible in response to tissue damage
or remodeling.

8. - Traditionally, signals have been
divided based on the cell of origin
into those that affect distant cells
(endocrine), nearby cells
(paracrine), or the same cell
(autocrine).

10. Receptors:
-The plasma membrane of eukaryotic cells
serves to insulate the cell from the outside
environment, but this barrier must be breached
to transmit signals of extracellular origin.
- This fundamental problem of transmitting
extracellular signals is solved in two ways:

11. 1. Signals cross the plasma membrane by
activating transmembrane receptors

12. 2. Using ligands that are membrane permeable

13. Receptors in Signal Transduction:
1) Receptor Tyrosine Kinases
2) Serine-Threonine Kinase Receptors
3) Receptor Phosphotyrosine Phosphatases
4) G protein-coupled receptors
5) Notch Family of Receptors
6) Guanylate Cyclases
7) Tumor Necrosis Factor Receptor Family
8) WNT Receptors
9) Nuclear Receptors
10)Adhesion Receptors

14. 1) Receptor Tyrosine Kinases
-Receptor tyrosine kinases are transmembrane
proteins that have an extracellular ligand-binding
domain, a transmembrane domain, and a
cytoplasmic tyrosine kinase domain.
- The ligands for these receptors are proteins or
peptides

15. - Most receptor tyrosine kinases are monomeric,
but members of the insulin-receptor family are
heterotetrameres in which the subunits are linked
by disulfide bonds.
- Examples of tyrosine kinase receptors include the
insulin receptor, the platelet-derived growth factor
(PDGF) receptor, the EGF receptor family, and the
fibroblast growth factor (FGF) receptor family.

16. - Activation of receptor tyrosine kinases generally
requires tyrosine phosphorylation of the receptor.
In the case of the insulin receptor, an insulin-
stimulated conformational change activates the
kinase. Most other tyrosine kinases are activated
by ligand-induced oligomerization, which brings
the kinase domains of distinct molecules into close
proximity so that they cross-phosphorylate.

19. Receptors in Signal Transduction:
1) Receptor Tyrosine Kinases
2) Serine-Threonine Kinase Receptors
3) Receptor Phosphotyrosine Phosphatases
4) G protein-coupled receptors
5) Notch Family of Receptors
6) Guanylate Cyclases
7) Tumor Necrosis Factor Receptor Family
8) WNT Receptors
9) Nuclear Receptors
10)Adhesion Receptors

20. 2) Serine-Threonine Kinase
Receptors
-The TGF-β receptors are transmembrane
proteins with intrinsic serine-threonine kinase
activity.
- There are two types; type I & II
- TGF-β ligands are dimers that bind to and
oligomerize type I and type II receptors.

21. - The type II receptors seem to be
constitutively active but do not
normally phosphorylate substrates,
whereas the type I receptors are
normally inactive
- Ligand-mediated dimerization of
the type I and type II receptors causes
the type II receptor to phosphorylate
the type I receptor

23. Receptors in Signal Transduction:
1) Receptor Tyrosine Kinases
2) Serine-Threonine Kinase Receptors
3) Receptor Phosphotyrosine Phosphatases
4) G protein-coupled receptors
5) Notch Family of Receptors
6) Guanylate Cyclases
7) Tumor Necrosis Factor Receptor Family
8) WNT Receptors
9) Nuclear Receptors
10)Adhesion Receptors

24. 3) Receptor Phosphotyrosine
Phosphatases
- Protein tyrosine phosphatases (PTPs) are a
group of enzymes that remove phosphate
groups from phosphorylated tyrosine residues on
proteins.
- They have an extracellular domain, a single
transmembrane-spanning domain, and
cytoplasmic catalytic domains.

25. -The extracellular domains of some receptor
tyrosine phosphatases contain fibronectin and
immunoglobulin repeats, suggesting that these
receptors may recognize adhesion molecules as
ligands.

27. - Functional and structural evidence suggests that
the phosphatase activity of some of these receptors
is inhibited by dimerization
- Ligand-dependent dimerization could cause
constitutively active tyrosine phosphatases to lose
activity, enhancing signals emanating from tyrosine
kinases.
- These enzymes are key regulatory components in
signal transduction pathways (such as the MAP
kinase pathway) and cell cycle control, and are
important in the control of cell growth,
proliferation and differentiation

29. Receptors in Signal Transduction:
1) Receptor Tyrosine Kinases
2) Serine-Threonine Kinase Receptors
3) Receptor Phosphotyrosine Phosphatases
4) G protein-coupled receptors
5) Notch Family of Receptors
6) Guanylate Cyclases
7) Tumor Necrosis Factor Receptor Family
8) WNT Receptors
9) Nuclear Receptors
10)Adhesion Receptors

30. 4) G protein-coupled
receptors (GPCRs)
-GPCRs are by far the most numerous receptors as
they encode the light, smell, and taste receptors.
-Examples include thrombin, neurotransmitters and
EGF receptors.
- Structurally GPCRs are characterized by an
extracellular N-terminus, followed by seven
transmembrane (7-TM) α-helices (TM-1 to TM-7)
connected by three intracellular (IL-1 to IL-3) and
three extracellular loops (EL-1 to EL-3), and finally
an intracellular C-terminus

32. - Intramolecular bonds involving
residues in the transmembrane or
juxtamembrane regions keep GPCRs in
an inactive conformation.
- In the inactive state, the receptor is
bound to a heterotrimeric G protein,
which is also inactive.
- Agonist binding causes a
conformational change that stimulates
the guanine nucleotide exchange activity
of the receptor. Exchange of guanosine
triphosphate (GTP) for guanosine
diphosphate (GDP) on the heterotrimeric
G proteins initiates signaling.

34. Receptors in Signal Transduction:
1) Receptor Tyrosine Kinases
2) Serine-Threonine Kinase Receptors
3) Receptor Phosphotyrosine Phosphatases
4) G protein-coupled receptors
5) Notch Family of Receptors
6) Guanylate Cyclases
7) Tumor Necrosis Factor Receptor Family
8) WNT Receptors
9) Nuclear Receptors
10)Adhesion Receptors

35. 5) Notch Family of Receptors
- The Notch receptor has a large extracellular domain,
a single transmembrane domain, and a cytoplasmic
domain.
-Ligands for the Notch receptor are proteins expressed
on the surface of adjacent cells, and activation results
in two proteolytic cleavages of Notch, releasing its
cytoplasmic region as a soluble signal
- This fragment moves to the nucleus, where it
complexes with a transcriptional repressor, relieving
its inhibitory effects and stimulating transcription

37. Receptors in Signal Transduction:
1) Receptor Tyrosine Kinases
2) Serine-Threonine Kinase Receptors
3) Receptor Phosphotyrosine Phosphatases
4) G protein-coupled receptors
5) Notch Family of Receptors
6) Guanylate Cyclases
7) Tumor Necrosis Factor Receptor Family
8) WNT Receptors
9) Nuclear Receptors
10)Adhesion Receptors

38. 6) Guanylate Cyclases
- Guanylate cyclases (GCs) convert GTP to cGMP
upon activation.
There are two forms of GCs:
Membrane GCs are receptors for atrial natriuretic
hormone, peptides that regulate intestinal secretion
and are necessary for regulating cGMP levels for
vision.
Soluble GCs are activated by nitrous oxide. These
receptors are widely expressed and regulate vascular
tone and neuron function.

40. Receptors in Signal Transduction:
1) Receptor Tyrosine Kinases
2) Serine-Threonine Kinase Receptors
3) Receptor Phosphotyrosine Phosphatases
4) G protein-coupled receptors
5) Notch Family of Receptors
6) Guanylate Cyclases
7) Tumor Necrosis Factor Receptor Family
8) WNT Receptors
9) Nuclear Receptors
10)Adhesion Receptors

41. 7) Tumor Necrosis Factor Receptor
Family
- The TNF family of receptors has a cysteine-rich
extracellular domain, a transmembrane domain, and a
death domain in the cytoplasm
-Receptors undergo oligomerization after ligand binding
- Stimulation of the receptor leads to recruitment of
cytoplasmic proteins that bind to each other and the
receptor through death domains, thereby activating a
protease, caspase 8 that initiates apoptosis
- Under some conditions, however, TNFRs may
stimulate antiapoptotic signals

43. Receptors in Signal Transduction:
1) Receptor Tyrosine Kinases
2) Serine-Threonine Kinase Receptors
3) Receptor Phosphotyrosine Phosphatases
4) G protein-coupled receptors
5) Notch Family of Receptors
6) Guanylate Cyclases
7) Tumor Necrosis Factor Receptor Family
8) WNT Receptors
9) Nuclear Receptors
10)Adhesion Receptors

44. 8) WNT Receptors
-The wnt family of growth and differentiation
factors consists of small proteins that bind to cell
surface receptors of the Frizzled family
-These receptors resemble GPCRs but utilize a
unique mechanism of signal transduction.
- Wnt proteins got their name from two of the first
to be discovered:
Wingless (wg) in Drosophila and its homolog
Int-1 in mice

45. - Binding of wnt to the receptor suppresses a
kinase cascade complex that involves many
proteins.
- This complex mediates phosphorylation and
ultimately proteosome-depend degradation of β-
catenin
- Suppression of β-catenin degradation in
response to wnt allows β-catenin to accumulate
in the cell and to migrate into the nucleus where
it regulates genes involved in cell growth
regulation

47. Receptors in Signal Transduction:
1) Receptor Tyrosine Kinases
2) Serine-Threonine Kinase Receptors
3) Receptor Phosphotyrosine Phosphatases
4) G protein-coupled receptors
5) Notch Family of Receptors
6) Guanylate Cyclases
7) Tumor Necrosis Factor Receptor Family
8) WNT Receptors
9) Nuclear Receptors
10)Adhesion Receptors

48. 9) Nuclear Receptors
-Ligands for nuclear receptors diffuse into the
cell and bind their receptors on the nucleus.
- The ligands include steroids, eicosanoids,
retinoids, and thyroid hormone.

49. - The receptors are transcription
factors that have both DNA- and
ligand-binding domains.
-The unliganded receptor is bound to
heat-shock proteins that are
dissociated after ligand binding.
-Release from the chaperone complex
and ligand association lead to binding
of the receptor to cofactors and DNA
to regulate transcription.

51. Chaperones are proteins that assist
the non-covalent folding or unfolding
and the assembly or disassembly of
other macromolecular structures, but
do not occur in these structures when
the structures are performing their
normal biological functions

52. Receptors in Signal Transduction:
1) Receptor Tyrosine Kinases
2) Serine-Threonine Kinase Receptors
3) Receptor Phosphotyrosine Phosphatases
4) G protein-coupled receptors
5) Notch Family of Receptors
6) Guanylate Cyclases
7) Tumor Necrosis Factor Receptor Family
8) WNT Receptors
9) Nuclear Receptors
10)Adhesion Receptors

53. 10) Adhesion Receptors
- Cell adherence, either to the extracellular matrix or to
other cells, is mediated by receptors that function
mechanically and stimulate intracellular signaling
pathways, primarily through tyrosine kinases
- Integrins mediate adherence to extracellular matrix
and are composed of heterodimers of α and β subunits.
- There is a ligand-binding site that binds the
extracellular matrix and a cytosolic domain that binds
the cytoskeleton.

54. - Interaction between the extracellular domain of
integrins and an extracellular ligand generate a variety
of signals.
- The interaction leads to clustering of integrins and the
rapid tyrosine phosphorylation of proteins at the
cytoplasmic face.
- Focal adhesion kinase (FAK) is an effector in
integrin-mediated responses.

56. Receptors in Signal Transduction:
1) Receptor Tyrosine Kinases
2) Serine-Threonine Kinase Receptors
3) Receptor Phosphotyrosine Phosphatases
4) G protein-coupled receptors
5) Notch Family of Receptors
6) Guanylate Cyclases
7) Tumor Necrosis Factor Receptor Family
8) WNT Receptors
9) Nuclear Receptors
10)Adhesion Receptors

57. SIGNALING!!