•
•
•
•
•

Polypeptides
Insulin glucagon somatotropin
Steroids
Estrogen testosterone cortisol
FSH
LH vasopressin
Aldosterone corticosterone
Progesterone
Oxytocin thyrotropin
ACTH
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 4
5
Glucagon
T-cell
Activation
Insulin
1
2
G
G protein
G
Cyclic AMP
Cyclic GMP
PK-A PK-G
3 4
G IP
3
G
Ca 2+ Diacylgycerol
5
Tyrosine kinase
Protein substrates
Calmodulin PK-C
Protein Ser/Thr kinases
Protein substrates
Protein substrates
Multifunctional kinases
End result is phosphorylation of one or more proteins Protein substrates
Other phospholipases

Releasing
Hypothalamus hormones
Anterior pituitary
Nervous
Posterior pituitary
Thyrotropin
Somatotropin
ACTH
LH
FSH
Prolactin
Vasopressin
Oxytocin
Thyroid
Adrenal
Cortex Pancreas Ovary Testis
T3
Cortisol aldosterone
Insulin, Estradiol Testosterone glucagon, somatostatin
Muscles liver Tissues
Liver, muscles
Adrenal
Medulla
Epinephrine
Reproductive organs
Mammary glands

Rule: Hormones elicit their own shut off mechanism
Hypothalamus
Corticotropin releasing factor
+
Anterior
Pituitary
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
Adenylate cyclase inhibit (Gi) c-AMP
Protein kinases

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

Resting
Active
Inactive
Resting
GDP
AC
ATP
GTP
AC cAMP
GDP
AC
GDP
PO
4
AC
GTP

hormone
Inhibitor
RS


AC
Ri
GDP
4 ATP
GTP
Adenylate cyclase
Signaling System
4 cAMP
AT P
Protein kinase
ADP
Inactive protein
Active protein
Cell response

N
Ligand
Cross phosphorylation
C
Tyrosine Kinase Receptors

Extracellular
Growth hormone
Extracellular domain of Growth Hormone Receptor
= O
3
PO-
Tyrosines
-OPO
3
=
Binding to receptor forces dimerization of receptor subunits for cross phosphorylation
Cell membrane (lipid bilayer)
Intracellular
Growth Hormone Receptor

Cell Signaling via RTK and
Ras
Kinases

• 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

• 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

• 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

Monday, May 10
10:30 a.m. – 12:30 p.m.