Hormones

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Hormones

Biochemical classification

Mechanism of action

Hierarchy

Feedback loops

Signal transduction

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

Cyclic AMP

G

Cyclic GMP

PK-A PK-G

3 4

G

Ca

2+

IP

3

G

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

Feedback Loops

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

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

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

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

• 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)

• 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.

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