Hormones

1. Hormones • Biochemical classification • Mechanism of action • Hierarchy • Feedback loops • Signal transduction

2. Polypeptides Oxytocin thyrotropin ACTH Insulin glucagon somatotropin FSH LH vasopressin Steroids Aldosterone corticosterone Progesterone Estrogen testosterone cortisol Amino acid derivatives Epinephrine norepinephrine dopamine Thyroxine, T3 and T4 Melatonin Serotonin

3. 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

4. 1 2 3 4 5 Nitric oxide T-cell Activation Glucagon Insulin 1 3 4 5 2 G G G IP3 G Tyrosine kinase G protein Protein substrates Cyclic GMP Ca2+ Diacylgycerol Cyclic AMP Calmodulin PK-C PK-A PK-G Protein Ser/Thr kinases Protein substrates Protein substrates Multifunctional kinases End result is phosphorylation of one or more proteins Other phospholipases Protein substrates

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

6. + + Feedback Loops Rule: Hormones elicit their own shut off mechanism Hypothalamus Anterior Pituitary Corticotropin releasing factor Adrenal Cortex -Corticotropin Cortisol

7. 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

8. Action 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

9. Cyclic AMP System Receptor G-protein Stimulate (Gs) and inhibit (Gi) Adenylate cyclase c-AMP Protein kinases

10. 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

11. GTP GDP GTP GDP GDP AC AC AC AC Resting ATP Active cAMP Inactive PO4 Resting

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

13. Ligand N Cross phosphorylation C Tyrosine Kinase Receptors

14. Extracellular Growth hormone Extracellular domain of Growth Hormone Receptor Binding to receptor forces dimerization of receptor subunits for cross phosphorylation =O3PO- -OPO3= Tyrosines Cell membrane (lipid bilayer) Intracellular Growth Hormone Receptor

15. Cell Signaling via RTK and Ras Kinases

16. 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.

17. Late Stage What is Behind the Biochemistry of Cancer? • 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 d. Ignore growth inhibitory signals e. Acquire vasculature (angiogenesis) – solid tumors f. Invade and colonize (metastasize) other tissue

18. 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)

19. 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

20. 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

21. 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

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