signal transduction for Medical students made by Ayman Mohammed Hany

1. Made by
Ayman Mohammed Hany
Lecturer of Medical Biochemistry and Molecular
Biology

2. Hormones are chemical
messengers that invoke
profound changes within
target cells.

4. Chemical messengers (also called signaling molecules)
transmit messages between cells.
They are secreted from one cell in response to a specific
stimulus and travel to a target cell where they bind to a
specific receptor and elicit a response.
In the nervous system, are called neurotransmitters
 In the endocrine system, they are hormones
 In the immune system, they are called cytokines.
Additional chemical messengers include retinoids,
eicosanoids, and growth factors.

5. Depending on the distance between the secreting
and target cells, chemical messengers can be
classified as :
Endocrine (travel in the blood),
Paracrine (travel between nearby cells)
Autocrine (act on the same cell that produces the
message).

6. Receptors are proteins that contain a
binding site specific for a single chemical
messenger and another binding site
involved in transmitting the message.

7. When a chemical messenger binds to a receptor, the signal
it is carrying must be converted into an intracellular
response.

8. the cell loses its responsiveness to new signals. Moreover,
signaling processes that fail to terminate properly can have
highly undesirable consequences. Many cancers are
associated with signal-transduction processes that are not
properly terminated, especially processes that control cell
growth.

11. (Intracellular Receptors)

12. 1. Steroid
2. Thyroid hormones
3. Calcitriol
4. Retinoids

13. The mechanism of action of these hormones
is to modulate gene expression in target cells
by binding to the receptor located inside
target cells, in the cytoplasm or nucleus, the
hormone-receptor complex binds to promoter
regions of responsive genes and stimulate or
inhibit transcription from those genes.

14. Receptors for the different hormones
have strong structural and functional
similarities which point to an evolution
from a common ancestral gene and
therefore are considered a gene
superfamily.

15.  Composed of a single polypeptide chain that has, in the simplest
analysis, three distinct domains:
1. The amino-terminus: in most cases, this region is involved in
activating or stimulating transcription by interacting with other
components of the transcriptional machinery. The sequence is
highly variable among different receptors.
2. DNA binding zinc finger domain: amino acids in this region are
responsible for binding of the receptor to specific sequences of
DNA.
3. The carboxy-terminus or ligand-binding domain: this is the region
that binds hormone.

16. specific sequences of DNA which are targeted by the
receptors

18. Step 1: Dissociation of hormone from the circulatory
transport protein
Step 2: Transport of the free hormone into cell cytosol or
nucleus
Step 3: Binding of hormone to the un-activated nuclear or
cytosolic receptor.
Step 4: Activation of hormone-receptor complex. (note-
when the hormone binds a cytosolic receptor, a heat-shock
protein is removed for the cytosolic receptor to be
activated).

19. Step5: Transport of the cytosolic hormone-receptor
complex to nucleus
Step 6: Activated hormone-receptor complex binds
DNA response elements (HRE}.
Step7: DNA transcribed into messenger RNA. mRNA
leaves nucleus, translated into protein on cytoplasmic
ribosomes.
Step 8: Newly made proteins elicit biological response

22.  1- Reception of the primary messenger. Most signal molecules
do not enter cells. Instead, proteins in the cell membrane act as
receptors that bind the signal molecules and transfer the
information that the molecule has bound from the environment
to the cell’s interior.
 Receptors span the cell membrane and thus have both
extracellular and intracellular components. A binding site on
the extracellular side specifically recognizes the signal
molecule (often referred to as the ligand). The interaction of
the ligand and the receptor alters the tertiary or quaternary
structure of the receptor so as to induce a structural change on
the intracellular side.

23. 2. Delivery of the Message Inside the Cell by the
Second Messenger. Other small molecules, called
second messengers, are used to relay information
from receptor–ligand complexes.
 Second messengers are intracellular molecules
that change in concentration in response to
environmental signals and mediate the next step
in the molecular information circuit.

24. 3. Activation of effectors That directly alter the
physiological response.
4. Termination of the Signal. After a cell has
completed its response to a signal, the signaling
process must be terminated or the cell loses its
responsiveness to new signals. Moreover, signaling
processes that fail to terminate properly can have
highly undesirable consequences.

25. Cell surface receptors are membrane proteins that have
regions that contribute to three basic domains:
1. Extracellular domains: hormone or ligand-binding
domain.
2. Transmembrane domains: serve to anchor the receptor
in the membrane.
3. Cytoplasmic or intracellular domains: lead to generation
of second messengers. Cytoplasmic residues of the
receptor are thus the effector region of the molecule.

26. Normal cell function depends upon
second messenger cascades being
transient events. Indeed, a number of
cancers are associated with receptors
that continually stimulate second
messenger systems.

27. One important part of negative regulation on
hormone action is that cell surface receptors are
internalized.
1. Endocytosis through structures called coated pits. The
resulting endosomes may fuse with lysosomes, leading
to destruction of the receptor and hormone.
2. The hormone dissociates and the receptor is recycled by
fusion of the endosome back into the plasma membrane.

34. cAMP can go into the nucleus and
phosphorylate the cAMP response element
binding protein (CREB) present in certain
genes. This protein is already bound to the
DNA. Phosphorylation of CREB leads to its
activation and promotes transcription.

35. Cholera and pertussis toxins
inactivate GTPase activity. The GTP-
α activity in affected cells is therefore
unopposed.

38. Cyclic GMP (cGMP) is generated from GTP By the
enzyme gaunylate cyclase(GC). There are two
forms of GC:
a-Soluble guanylyl cyclase(sGC): stimulated by
nitric oxide (NO), and nitoglycerin, sodium
nitroprusside and azide.
b-Membrane bound guanylyl cyclase stimulated by
Atriopeptins [eg,Atrial naturetic peptide(ANP)]

39. -Inhibitors of cGMP phosphodiesterase (the enzyme which
degrades cGMP into GMP) act by increasing cyclic GMP. An
example is the drug Sildenafil used to treat erectile dysfunction.

40. Many chemical transmitters
1. Acetylcholine
2. Histamine
3. Serotonin
Hormones
1. vasopressin
2. α-1 receptors for epinephrine and norepinephrine

42. The insulin and IGF-I and some growth
factor receptors contain intrinsic ligand-
activated tyrosine kinase activity.
 The ligand-receptor interaction that results
in a tyrosine phosphorylation event initiates
a cascade that may involve several protein
kinases, phosphatases, and other regulatory
proteins.

44. The receptor is a tetramer linked by disulfide
bonds.
It is formed of 2α (extra-cellular domains)
and 2β subunits (trans-membrane domains).
Binding of insulin to the α-subunits
stimulates the tyrosine kinase activity of β-
subunits causing autophosphorylation of
tyrosine residues of the β-subunits

45. The phosphorylated insulin receptor next phosphorylates
signal protein molecules named insulin-receptor
substrates (IRSs) on tyrosine residues.
 There are at least four of these molecules, called IRS 1–4.
Phosphorylated of IRS proteins produces interaction with
other signalling proteins that mediate insulin action (gene
expression, cell metabolism and growth).
These signalling proteins have a characteristic domain in
their structure called the SH2 or src homology domain.

46. 1- Activation of phosphatidyl inositol-3(PI-3) kinase pathway
which propagates the signal through a cascade of kinases. This
finally ends in
a) Translocation of GLUT4 to the cell membrane
b) Activates phosphodiesterases and phosphatases that
mediate the action of insulin on carbohydrate and lipid
metabolism.
2- Binding to growth factor receptor binding protein (GRB2)
activating a group of other kinases, which leads to activation of
mitogen-activated protein kinase (MAPK). This mediates the
action of insulin on DNA synthesis, cell proliferation and
differentiation.

47. The action of insulin is terminated by
dephosphorylation of the receptor. Binding of
insulin to its membrane receptors is followed by
internalization of the hormone-receptor complex
then insulin is degraded in the lysosomes.
Defect in the insulin receptor or post-receptor
molecules results in signal transduction defects
leading to insulin resistance.