Download Hormones

Hormones
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Biochemical classification
Mechanism of action
Hierarchy
Feedback loops
Signal transduction
Polypeptides
Insulin
glucagon
somatotropin
Steroids
Estrogen
testosterone
cortisol
FSH
LH
vasopressin
Oxytocin
thyrotropin
ACTH
Aldosterone
corticosterone
Progesterone
Amino acid derivatives
Epinephrine
norepinephrine
dopamine
Thyroxine, T3 and T4
Melatonin
Serotonin
Rule: All hormones interact with target cells by
first binding to specific receptors located either on
the plasma membrane or as a cytosolic protein
Rule: The receptor for hormones must be linked
to a component that is able to respond to the
binding of hormone with its receptor
Rule: Substances that fool the responder into
thinking a hormone has bound are call agonists
Rule: Substances that prevent the binding of the
natural hormone and do not elicit a response from
the receptor are called antagonists
1
2
Nitric
oxide
3
5
4
T-cell
Activation
Glucagon
1
3
2
G
G protein
Cyclic AMP
G
G
Cyclic GMP
PK-A
PK-G
4
IP3
Insulin
5
G
Ca2+
Diacylgycerol
Calmodulin
PK-C
Tyrosine
Protein kinase
substrates
Protein Ser/Thr
kinases
Protein substrates
End result is
phosphorylation of
one or more proteins
Multifunctional
kinases
Protein substrates
Protein substrates
Other
phospholipases
Hypothalamus
Releasing
hormones
Anterior pituitary
Nervous
Posterior pituitary
Thyrotropin
Somatotropin
FSH
Vasopressin
Prolactin
LH
Oxytocin
ACTH
Adrenal
Thyroid Cortex Pancreas Ovary
T3
Testis
Cortisol
Insulin,
Estradiol Testosterone
aldosterone glucagon,
somatostatin
Muscles
liver
Tissues
Liver,
muscles
Adrenal
Medulla
Epinephrine
Reproductive Mammary
organs
glands
Feedback Loops
Rule: Hormones elicit their own shut off mechanism
Hypothalamus
Anterior
Pituitary
Corticotropin
releasing factor +
Adrenal
Cortex
-Corticotropin
+
Cortisol
Rule: All peptide hormones are synthesized as
inactive “pre-pro” precursors
Rule: A signal peptide must be cleaved off to
activate the mature form of the hormone
Signal Transduction
Definition: The series events and components that
take part in transmitting a hormonal signal to a
the interior of the cell
Membrane or cytosolic Receptor
Signal Initiator
Signal mediator
Target molecule
Action
Cyclic AMP System
Receptor
G-protein
Stimulate (Gs) and
inhibit (Gi)
Adenylate cyclase
c-AMP
Protein kinases
G-Proteins
A family of membrane proteins that exist in an inactive
(GDP) and an active (GTP) state
So-named because they bind GTP, displacing GDP
Work with many receptors
Both Stimulate and inhibit hormone signals
GTP is a time-bomb slowly ticking
When GTP is hydrolyzed to GDP, stimulation is stopped
GTP
GDP
AC
Resting
ATP
GTP
Active
AC
cAMP
GDP
Inactive
AC
PO4
Resting
GDP
AC
hormone
Inhibitor
Ri
RS
GTP
GDP 

GTP
AC

GDP
4 ATP
AT
4 cAMP
Adenylate cyclase
Signaling System
P
Protein
kinase
Inactive
protein
ADP
Active
protein
Cell response
N
Ligand
Cross
phosphorylation
C
Tyrosine Kinase Receptors
Extracellular
Growth hormone
Extracellular domain
of Growth Hormone Receptor
=O
3PO-
-OPO3=
Tyrosines
Intracellular
Binding to receptor forces
dimerization of receptor
subunits for cross
phosphorylation
Cell membrane (lipid bilayer)
Growth Hormone Receptor
Cell Signaling
via RTK and
Ras
Kinases
Challenge to Students
• Many of the proteins that you just saw are coded
by genes referred to as “oncogenes”, meaning they
are capable of transforming a normal cell into a
cancer cell. Src, Ras, ErbB, affect cell growth and
differentiation.
• The viral forms of these genes lack regulation, and
the mammalian form (proto-oncogenes) are
subject to mutation.
• If you want to learn what causes a normal cell to
become a cancer cell (malignant transformation),
this is a good place to start.
What is Behind the Biochemistry of Cancer?
1. An alteration of genes/proteins involved in:
a. Cell proliferation
b. Apoptosis (programmed cell death)
c. Differentiation
2. Acquisition of a phenotype that allows cells to:
a. Proliferate without limits
b. Evade apoptosis
c. Generate its own mitogenic signals
Late
Stage
d. Ignore growth inhibitory signals
e. Acquire vasculature (angiogenesis) – solid tumors
f. Invade and colonize (metastasize) other tissue
Genes Mutated
1. ras protein (25% of cancers)
2. p53 tumor suppressor (50% of cancers)
a. controls DNA repair
b. controls apoptosis
3. Tyrosine kinase receptor (HER2/neu)
a. controls ras (overexpression)
We Know
1. Biochemical pathways from ras to p53
2. Role of p53 in apoptosis and DNA repair
We Don’t Know
1. Molecular circuitry for enhancing secretion of
angiogenic factors from cancer cells
2. The regulation of elements controlling the migration
and extravastion capabilities of cancer cells
Take Home
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Most hormones never penetrate cells
All hormones have receptors
Internal responses are initiated by the receptor
Receptors work with G proteins
G proteins stimulate protein kinases
Protein kinases comprise a cell signaling
cascade
• G proteins turn off when GTP is hydrolyzed to
GDP, canceling the hormone action
Take Home (Part 2)
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Some receptors are protein tyrosine kinases
Kinase activity is initiated by dimerization
Kinase autophosphorylate receptors
Phosphotyrosines bind to SH-2 domains
Activation starts a kinase cascade
Phosphorylated proteins enter nucleus
DNA transcription turns on specific genes
Final Exam
Monday, May 10
10:30 a.m. – 12:30 p.m.