Hormones Biochemical classification Mechanism of action Hierarchy Feedback loops Signal transduction

Polypeptides Steroids Amino acid derivatives Insulin glucagon somatotropin FSH LH vasopressin Oxytocin thyrotropin ACTH Estrogen testosterone cortisol Aldosterone corticosterone Progesterone 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

Cyclic AMP Cyclic GMP Ca 2+ Diacylgycerol Protein substrates PK-APK-G CalmodulinPK-C Protein Ser/Thr kinases Protein substrates Multifunctional kinases Other phospholipases Tyrosine kinase IP 3 GGGG Insulin Glucagon T-cell Activation Nitric oxide G protein End result is phosphorylation of one or more proteins

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

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

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

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

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

Tyrosine Kinase Receptors Ligand N C Cross phosphorylation

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

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 d. Ignore growth inhibitory signals e. Acquire vasculature (angiogenesis) – solid tumors f. Invade and colonize (metastasize) other tissue Late Stage

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 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 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.