Hormones

• Biochemical classification

• Mechanism of action

• Hierarchy

• Feedback loops

• Signal transduction

PolypeptidesPolypeptides

SteroidsSteroids

Amino acid derivativesAmino acid derivatives

Insulinglucagonsomatotropin

FSHLHvasopressin

OxytocinthyrotropinACTH

Estrogentestosteronecortisol

AldosteronecorticosteroneProgesterone

Epinephrinenorepinephrinedopamine

Thyroxine, T3 and T4MelatoninSerotonin

Rule: All hormones interact with target cells by first binding to specific receptors located either onthe plasma membrane or as a cytosolic protein

Rule: The receptor for hormones must be linkedto a component that is able to respond to thebinding of hormone with its receptor

Rule: Substances that fool the responder intothinking a hormone has bound are call agonists

Rule: Substances that prevent the binding of thenatural hormone and do not elicit a response fromthe receptor are called antagonists

Cyclic AMP Cyclic GMP Ca2+ Diacylgycerol Proteinsubstrates

PK-A PK-G Calmodulin PK-CProtein Ser/Thr kinases

Protein substrates

Protein substrates

Protein substratesMultifunctional kinases

Otherphospholipases

1 2 3 4 5

11 2 3 4 5

Tyrosine kinase

IP3G G G G

InsulinGlucagon T-cellActivation

Nitricoxide

G protein

End result is phosphorylation ofone or more proteins

Hypothalamus

Anterior pituitaryPosterior pituitary

Thyrotropin

ACTH

Somatotropin

LH

FSHProlactin

Vasopressin

Oxytocin

ThyroidAdrenalCortex

AdrenalMedullaPancreas Ovary Testis

Muscles liver Tissues

Liver,muscles

Estradiol TestosteroneInsulin,glucagon,somatostatin

T3 Cortisolaldosterone

Mammary glands

Reproductive organs

Epinephrine

Releasinghormones

Nervous

Feedback Loops

Rule: Hormones elicit their own shut off mechanism

Hypothalamus

Corticotropinreleasing factor

AnteriorPituitary

-Corticotropin

Cortisol

AdrenalCortex+

+

Rule: All peptide hormones are synthesized asinactive “pre-pro” precursors

Rule: All peptide hormones are synthesized asinactive “pre-pro” precursors

Rule: A signal peptide must be cleaved off to activate the mature form of the hormone

Rule: A signal peptide must be cleaved off to activate the mature form of the hormone

Signal Transduction

Definition: The series events and components thattake part in transmitting a hormonal signal to athe interior of the cell

Definition: The series events and components thattake part in transmitting a hormonal signal to athe interior of the cell

Membrane or cytosolic Receptor

Signal Initiator

Target molecule

Signal mediator

Action

Cyclic AMP System

Receptor

Adenylate cyclase

G-protein

Protein kinases

c-AMP

Stimulate (Gs) and inhibit (Gi)

G-Proteins

So-named because they bind GTP, displacing GDP

Work with many receptors

Both Stimulate and inhibit hormone signals

A family of membrane proteins that exist in an inactive(GDP) and an active (GTP) state

GTP is a time-bomb slowly ticking

When GTP is hydrolyzed to GDP, stimulation is stopped

GTPAC

GDP

ACGTP

ACGDP

GDPAC

Resting

Active

Inactive

Resting

ATP

cAMP

PO4

GTP

GDP

GDPGTP

4 ATP

4 cAMP

Cell response

AT

Protein kinase

ADP

PInactive protein

Active protein

hormone

Adenylate cyclase Signaling System

AC

RS

Inhibitor

Ri

Tyrosine Kinase Receptors

LigandN

C

Cross phosphorylation

Cell membrane (lipid bilayer)

Growth hormone

Extracellular domainof Growth Hormone Receptor

Intracellular

Extracellular

Growth Hormone Receptor

Binding to receptor forces dimerization of receptor

subunits for cross phosphorylation

-OPO3=

=O3PO-

Tyrosines

Cell Signalingvia 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 limitsb. Evade apoptosis

c. Generate its own mitogenic signals

d. Ignore growth inhibitory signalse. Acquire vasculature (angiogenesis) – solid tumors

f. Invade and colonize (metastasize) other tissueLate Stage

Genes Mutated1. 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 Know1. Biochemical pathways from ras to p53

2. Role of p53 in apoptosis and DNA repair

We Don’t Know1. 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 HomeTake 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

• 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)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

• 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.