Hormones and Signal Transduction...

Hormones and Signal Transduction II

Dr. Kevin Ahern

Hormones and Signal Transduction• G-Protein Coupled Receptors Outline

Receptor G-Proteins Protein Kinase A Kinase Cascade Turning Signal Off The Coffee Connection

Hormones and Signal Transduction• β-adrenergic Receptor Signaling

ATPcAMP

PKA-RegPKA

GS-P GSPKPK-P

GP-bP-GP-a

GlycogenxGlycogenx-1

Glucose-1-phosphate

ATPcAMP

PKA-RegPKA

GS-P GSPKPK-P

GP-bP-GP-a

Glucose-1-phosphate

ATPcAMP

PKA-RegPKA

GS-P GSPKPK-P

GP-bP-GP-a

Glucose-1-phosphate

ATPcAMP

PKA-RegPKA

GS-P GSPKPK-P

GP-bP-GP-a

Glucose-1-phosphate

ATPcAMP

PKA-RegPKA

GS-P GSPKPK-P

GP-bP-GP-a

Glucose-1-phosphate

Protein Kinase A

ATPcAMP

PKA-RegPKA

GS-P GSPKPK-P

GP-bP-GP-a

Glucose-1-phosphate

5Protein Kinase A

Phosphorylase Kinase

ATPcAMP

PKA-RegPKA

GS-P GSPKPK-P

GP-bP-GP-a

Glucose-1-phosphate

55aProtein Kinase A

Phosphorylase KinaseGlycogen Synthase

ATPcAMP

PKA-RegPKA

GS-P GSPKPK-P

GP-bP-GP-a

Glucose-1-phosphate

Protein Kinase A

Glycogen Phosphorylase

Glycogen Synthase

ATPcAMP

PKA-RegPKA

GS-P GSPKPK-P

GP-bP-GP-a

Glucose-1-phosphate

Protein Kinase A

Glycogen Phosphorylase

Glycogen Synthase

Hormones and Signal Transduction• PKA Activation

Hormones and Signal Transduction• Turning Off β-adrenergic Receptor Signaling

Turning off the Signaling Pathway

β-adrenergic Receptor

β-adrenergic ReceptorG-Protein

β-adrenergic ReceptorG-ProteincAMP

β-adrenergic ReceptorG-ProteincAMPProtein Kinase A

Turning Off β-adrenergic Receptor

Turning Off β-adrenergic ReceptorExterior of Cell

Cytoplasm

G-Protein Receptor Kinase

ATP ADP

Exterior of Cell

Cytoplasm

ArrestinG-Protein Receptor Kinase

ATP ADP

Exterior of Cell

Cytoplasm

ATP ADP

Exterior of Cell

Cytoplasm

Blocks andFavors Endocytosis

ATP ADP

Exterior of Cell

Cytoplasm

G-protein Inactivation

Auto-regulating

Auto-regulatingInherent GTPase Activity

Hydrolysis

Phosphate

Hydrolysis

Phosphate

Hydrolysis

Phosphate

Hydrolysis

Phosphate

Hydrolysis

Phosphate

Return to Resting State

Hydrolysis

Phosphate

Return to Resting State

Adenylate Cyclase Inactivated - no more cAMP

GS-PPK-P

P-GP-a

Glucose-1-phosphate

GS-PPK-P

P-GP-a

Glucose-1-phosphate

Phosphodiesterase

GS-PPK-P

P-GP-a

Glucose-1-phosphate

Phosphodiesterase

GS-PPK-P

P-GP-a

Glucose-1-phosphate

Phosphodiesterase

Becomes Inactive

GS-PPK-P

P-GP-a

Glucose-1-phosphate

Phosphodiesterase

GS-PPK-P

P-GP-a

Glucose-1-phosphate

Phosphodiesterase

Phosphodiesterase is Inhibited by Caffeine

GS-PPK-P

P-GP-a

Glucose-1-phosphate

Phosphodiesterase

Phosphodiesterase is Inhibited by Caffeine

Drinking Coffee Givesa Small Boost to

Blood Glucose by Keeping cAMP Levels

Higher

GS-PPK-P

P-GP-a

Glucose-1-phosphate

Receptor Tyrosine Kinases (RTKs)

RTKs are Membrane Bound Proteins that Phosphorylate Tyrosines

RTKs are Membrane Bound Proteins that Phosphorylate TyrosinesRTKs Play Important Roles in Regulating Cell Proliferation

RTKs are Membrane Bound Proteins that Phosphorylate TyrosinesRTKs Play Important Roles in Regulating Cell ProliferationDimerization Important for Activity

ATP ADP

Lipid Bilayer

Outside of Cell

Inside of Cell (Cytoplasm)

Lipid Bilayer

Outside of Cell

RTK Monomer RTK Monomer

Lipid Bilayer

Outside of Cell

Transmembrane α-helix

Lipid Bilayer

Outside of Cell

Transmembrane α-helix Cytoplasmic Tyrosine Kinase Domain

(inactive)

Ligand (Hormone) Binding &

Dimerization

Activation of Tails Autophosphorylation

Dimerization

Activation of Tails Autophosphorylation P

Dimerization

Activation of Tails Autophosphorylation P

PP Active Tyrosine

Kinase

Assembly of Signaling Complex

PPPP P

SH2 Domains of Proteins Recognize and Bind Phosphotyrosines

PPPP P

Signaling Complex Communicates Message to

Cell (usually by phosphorylation)

SH2 Domains of Proteins Recognize and Bind Phosphotyrosines

• RTK Signaling OverviewReceptor Tyrosine Kinases (RTKs)

• RTK Signaling Overview

Binding of Hormone to RTK in Membrane

Receptor Dimerization

Autophosphorylation

Signaling Complex Assembly

Autophosphorylation

Signaling Complex Assembly

Communicate Message

to Cell

RTKs -‐ Insulin Receptor

Unlike Other RTKs, Always a Dimer in Membrane

Unlike Other RTKs, Always a Dimer in MembraneBinding of Insulin Activates Autophosphorylation of Tails

Binding of Insulin

Autophos- phorylation

Binding of Insulin

IRS-1 Activation

Binding of Insulin

IRS-1 Activation

PI3 Kinase Activation

Other Signaling Pathways

Binding of Insulin

IRS-1 Activation

PIP3 Formation

Binding of Insulin

IRS-1 Activation

PIP3 Formation

PDK1 Activation

Binding of Insulin

IRS-1 Activation

PIP3 Formation

PDK1 Activation

Akt Kinase Activation

Binding of Insulin

IRS-1 Activation

PIP3 Formation

PDK1 Activation

Stimulate GLUT4

Movement to Cytoplasm

Binding of Insulin

IRS-1 Activation

PIP3 Formation

PDK1 Activation

Stimulate GLUT4

Cells Uptake Glucose

Binding of Insulin

IRS-1 Activation

PIP3 Formation

PDK1 Activation

Stimulate GLUT4

Blood Glucose Levels

Binding of Insulin

IRS-1 Activation

PIP3 Formation

PDK1 Activation

Stimulate GLUT4

Blood Glucose Levels

Insulin Signaling AlsoActivates

PhosphoproteinPhosphatase

Hormones and Signal Transduction

Insulin Receptor Pathway

β- Adrenergic Pathway

β- Adrenergic PathwayG-Protein

Adenylate Cylase

PKA Active

PK Active

GS Inactive

GP-a Active

Adenylate Cylase

PKA Active

PK Active

GS Inactive

GP-a Active

Glycogen Broken Down

Blood Glucose Levels Rise

Adenylate Cylase

PKA Active

PK Active

GS Inactive

GP-a Active

Blood Glucose Levels RiseTyrosine Kinase Activation

IRS-1 Activation

PIP3 Formation

PDK1 Activation

GLUT4 Moved to Cytoplasm

Phosphoprotein Phosphatase Activated

Glucose Taken Into Cell

PK, GP-a Inactive GS Active

Adenylate Cylase

PKA Active

PK Active

GS Inactive

GP-a Active

Blood Glucose Levels RiseTyrosine Kinase Activation

IRS-1 Activation

PIP3 Formation

PDK1 Activation

GLUT4 Moved to Cytoplasm

Phosphoprotein Phosphatase Activated

Glucose Taken Into Cell

PK, GP-a Inactive GS Active

Blood Glucose Levels Fall

Glycogen Made

RTKs -‐ Epidermal Growth Factor

Receptor Tyrosine Kinase

Receptor Tyrosine KinaseDimerizes on Binding Epidermal Growth Factor (EGF)

Receptor Tyrosine KinaseDimerizes on Binding Epidermal Growth Factor (EGF)Involved in Growth, Proliferation and Cell Differentiation

Epidermal Growth Factor Receptor (EGFR)RTKs -‐ Epidermal Growth Factor

EGFR Signaling, Part 1Epidermal Growth Factor Receptor (EGFR)

EGFR Dimer

Autophosphorylated Tyrosines in

Cytoplasmic Domain

EGFR Dimer

Cytoplasmic Domain

Signaling Complex Assembled on

Phosphotyrosines

EGFR Dimer

Cytoplasmic Domain

Phosphotyrosines

GTP GDP

EGFR Dimer

Cytoplasmic Domain

Phosphotyrosines

GTP GDP

EGFR Dimer

Cytoplasmic Domain

Phosphotyrosines

GTP GDP

Prepares Cell for Division

Metabolic Melody

In My Liver (to the tune of “And I Love Her”)

If I am missing meals

On busy days

That’s when my body steals

Glucose away

From my liver

It starts with glucagon

When I’m weak kneed

The hormone acts to spawn

New energy

In my liver

Bridge

The signaling

Acts rapidly

c-A-M-P’s

Fire up kinase

If I am missing meals

On busy days

That’s when my body steals

Glucose away

From my liver

It starts with glucagon

When I’m weak kneed

The hormone acts to spawn

New energy

In my liver

Bridge

The signaling

Acts rapidly

c-A-M-P’s

Fire up kinase

Phosphorylase then gets

Re-activated

So glycogen begets

Glucose phosphated

In my liver

Instrumental

Then in the last step here

A phosphatase

Makes phosphate disappear

With no delays

In my liver

Hormones and Signal Transduction...

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