Hormones and Signal Transduction III - Oregon State...

Hormones and Signal Transduction III

Dr. Kevin Ahern

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

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

RTKs -‐ Epidermal Growth Factor


EGFR Dimer



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

GTP



EGFR Dimer


Cytoplasmic Domain


Phosphotyrosines

GTP GDP

GTP

Prepares Cell for Division



RAS Activates RAF Kinase



RAF/RAS Activates MEK Kinase




MEK Activates MAP Kinase Cascade




Transcription Factor Phosphorylation

Activates Gene Expression

MEK Activates MAP Kinase Cascade


RAS

RAS

RAS is a Family of Related Proteins

RAS

RAS is a Family of Related ProteinsEach is Monomeric and like the α-subunit of G-Proteins

RAS

RAS is a Family of Related ProteinsEach is Monomeric and like the α-subunit of G-ProteinsRAS Proteins Bind Guanine Nucleotides

RAS


Human r-RAS

RAS


Human r-RAS

Bound GDP

RAS

RAS is a Family of Related ProteinsEach is Monomeric and like the α-subunit of G-ProteinsRAS Proteins Bind Guanine NucleotidesRAS Swaps GDP for GTP on Activation

Human r-RAS

Bound GDP

RAS

RAS is a Family of Related ProteinsEach is Monomeric and like the α-subunit of G-ProteinsRAS Proteins Bind Guanine NucleotidesRAS Swaps GDP for GTP on ActivationRAS Slowly Cleaves GTP to GDP

Human r-RAS

Bound GDP

RTKs Summary

RTKs Summary

Dimerization is Important for RTK Activation RTKs Play Important Roles in Regulating Cell Proliferation Binding of Ligand Causes Dimerization for Most RTKs Dimerization Causes Cytoplasmic Tails to Autophosphorylate and Activate A Signaling Complex Binds to Phosphotyrosines and Communicates Message to

Cell (usually by phosphorylation) The Insulin Receptor is a RTK that Stimulates Movement of GLUT4 to Membranes Insulin Signaling Stimulates Phosphoprotein Phosphatase Phosphoprotein Phosphatase Reverses Effects of Epinephrine Insulin Signaling Favors Reduced Blood Glucose and Glycogen Synthesis Epinephrine Signaling Favors Increased Blood Glucose and Glycogen Breakdown EGFR Dimerizes and Activates on Binding EGF EGF Signaling Activates Transcription and Favors Cell Division RAS is Like a G-Protein and Activates Cell Division When Bound to GTP Turning off EGFR Signaling Involves GTPase (Ras), Phosphatases, and Endocytosis of

Receptors

Steroid Hormone Signaling

Steroid Hormones Control Metabolism, Inflammation, Immune Functions, Water/salt Balance,Sexual Characteristics, and Response to Illness/Injury



Steroid Signaling Uses Intracellular, Non-membrane Receptors



Steroid Signaling Uses Intracellular, Non-membrane ReceptorsFive Classes of Steroid Hormones in Two Groups - Corticosteroids and Sex Hormones



Steroid Signaling Uses Intracellular, Non-membrane ReceptorsFive Classes of Steroid Hormones in Two Groups - Corticosteroids and Sex HormonesSignaling Mostly Affects Gene Expression so Tends to be Slower in its Effects




Steroid Hormone Released into Blood


Steroid Hormone Released into BloodCrosses Lipid Bilayer of Target Cell


Steroid Hormone Released into BloodCrosses Lipid Bilayer of Target CellBinds to Internal Receptor


Steroid Hormone Released into BloodCrosses Lipid Bilayer of Target CellBinds to Internal ReceptorInternal Receptor Changes Shape,

Becoming Transcription Factor


Steroid Hormone Released into BloodCrosses Lipid Bilayer of Target CellBinds to Internal ReceptorInternal Receptor Changes Shape,

Becoming Transcription FactorTranscription Factor Alters Cell’s

Gene Expression

Cell

Nucleus


Cell

Nucleus

Lipid Bilayer


Cell

Nucleus

Lipid Bilayer

Receptor Bound to Hsp70


Cell

Nucleus

Lipid Bilayer

1

1. Hormone Arrives in Blood Receptor Bound to Hsp70


Cell

Nucleus

Lipid Bilayer

1

1. Hormone Arrives in Blood2

2. Movement Across Lipid Bilayer



Cell

Nucleus

Lipid Bilayer

1



3

3. Hormone Binds Receptor, Hsp70

Released



Cell

Nucleus

Lipid Bilayer

1



3


Released

4

4. Movement of Hormone-bound

Receptor to Nucleus



Cell

Nucleus

Lipid Bilayer

1



3


Released

4

4. Movement of Hormone-bound

Receptor to Nucleus

5. Transcription

5. Hormone-bound Receptor Binds DNA, Initiates Transcription




Glucocorticoid Hormone Signaling



Hormone Entry



Hormone EntryHSP Release




Dimerization




Dimerization Movement to Nucleus




Dimerization Movement to Nucleus

Transcription Activation

Hormones and Signal Transduction• Non-Hormone Signaling


Cells Communicate in Other Ways Than With Hormones


Cells Communicate in Other Ways Than With HormonesNerve Transmission



Relies on Ion Gradients and Neurotransmitter Molecules to Transmit Signal



Relies on Ion Gradients and Neurotransmitter Molecules to Transmit SignalBlocked by Ion Channel Blocking Molecules




Prostanoids




Prostanoids Derived from Arachidonic Acid and Exert Effects Near Where They are Released - Prostaglandins, Prostacyclin and Thromboxanes

Prostaglandin H2 Thromboxane A2




Prostanoids Derived from Arachidonic Acid and Exert Effects Near Where They are Released - Prostaglandins, Prostacyclin and ThromboxanesSynthesis Inhibited by Steroids and NSAIDs - Aspirin, Ibuprofen

Prostaglandin H2 Thromboxane A2

Signaling Gone Wild• Signaling Gone Wild


Signaling Proteins Play Important Roles in Growth and Division


Signaling Proteins Play Important Roles in Growth and DivisionOncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled Growth


Signaling Proteins Play Important Roles in Growth and DivisionOncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled GrowthProto-Oncogene - Unmutated Form of an Oncogene


Signaling Proteins Play Important Roles in Growth and DivisionOncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled GrowthProto-Oncogene - Unmutated Form of an Oncogene


Signaling Proteins Play Important Roles in Growth and DivisionOncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled GrowthProto-Oncogene - Unmutated Form of an OncogeneMutations in Signaling Systems Can Lead to Tumor Formation



Mutations Affecting Protein Structure/Function



Mutations Affecting Protein Structure/FunctionMutations Affecting Expression of Protein



Mutations Affecting Protein Structure/FunctionMutations Affecting Expression of ProteinOther Mutations

Hormones and Signal Transduction• Signaling Gone Wild


RAS



RAS1. GDP Bound RAS Inactive




2. GTP Binding Activates





3. GTPase Converts GTP to GDP, Inactivating





3. GTPase Converts GTP to GDP, Inactivating4. Mutations of Amino Acids 11/12 or 61 Inhibit GTPase & Activate RAS





3. GTPase Converts GTP to GDP, Inactivating4. Mutations of Amino Acids 11/12 or 61 Inhibit GTPase & Activate RAS5. Activated RAS Stimulates Cell Division






Mutated RAS Most Common Point Mutation in Cancer






Mutated RAS Most Common Point Mutation in Cancer

Mutated RAS in 90% of Pancreatic Cancer and 20% of all Cancers



Not All Tyrosine Kinases are RTKs


Not All Tyrosine Kinases are RTKsSrc Proteins are Tyrosine Kinases Found in Various

Cell Locations

Src



Cell LocationsDephosphorylated Src Acts to Stimulate Cell Division

Src



Cell LocationsDephosphorylated Src Acts to Stimulate Cell DivisionPhosphorylation of Src’s Tyrosines Turns it OFF

Src



Cell LocationsDephosphorylated Src Acts to Stimulate Cell DivisionPhosphorylation of Src’s Tyrosines Turns it OFFMutations that Affect Src’s Phosphorylation Convert

Src



Cell LocationsDephosphorylated Src Acts to Stimulate Cell DivisionPhosphorylation of Src’s Tyrosines Turns it OFFMutations that Affect Src’s Phosphorylation Convert

it to an Oncogene

Src



Src



Src

Src



Src

SrcPhosphorylated Tyrosines Block Access to its SH2 Domain and Prevent it From Participating in Signaling Leaving it Inactive



Src

SrcPhosphorylated Tyrosines Block Access to its SH2 Domain and Prevent it From Participating in Signaling Leaving it Inactive

Mutations Changing These Tyrosines Leave the Protein Always Activated, Stimulating Uncontrolled Cell Division

Hormones and Signal Transduction• Introduction

HER2-Herceptin Complex

Mutations Affecting Expression of Protein



HER2 Doesn’t Require EGF Binding for Dimerization/Activation




HER2 Doesn’t Require EGF Binding for Dimerization/ActivationIs Always Signaling Cell to Divide When Dimerized





Mutations Increasing Levels of HER2 Found in Several Cancers





Mutations Increasing Levels of HER2 Found in Several CancersBreast Cancer (15-30%)






Ovarian Cancer






Ovarian CancerStomach Cancer






Ovarian CancerStomach CancerUterine Cancer







Treated with Monoclonal Antibody - Herceptin







Treated with Monoclonal Antibody - HerceptinHerceptin Binds HER2’s Extracellular Domain to Prevent Dimerization



Other Mutations


Other Mutations

Bcr-Abl Fusion

Chromosomes 9 & 22

abl

bcr

22

9


Other Mutations

Bcr-Abl Fusion

Chromosomes 9 & 22

abl

bcr

22

9

Crossover


Other Mutations

Bcr-Abl Fusion

Chromosomes 9 & 22

abl

bcr

22

9

Fusion Chromosomes

9/22

22/9

bcr-abl fusion


Other Mutations

Bcr-Abl Fusion

Chromosomes 9 & 22

abl

bcr

22

9

Fusion Chromosomes

9/22

22/9

bcr-abl fusion

The bcr-abl fusion links the tyrosine kinase of abl with the N-terminus

and transcription control of bcr


Other Mutations

Bcr-Abl Fusion

Chromosomes 9 & 22

abl

bcr

22

9

Fusion Chromosomes

9/22

22/9

bcr-abl fusion

The bcr-abl fusion links the tyrosine kinase of abl with the N-terminus

and transcription control of bcr

All regulation of abl is lost in the fusion, so the

bcr-abl fusion is signaling ‘division’ all the time



Bcr-Abl Fusion


Bcr-Abl FusionAlso Known as Philadelphia Translocation


Bcr-Abl FusionAlso Known as Philadelphia TranslocationPresent in 95% of people with CML (Chronic Myelogenous Leukemia)


Bcr-Abl FusionAlso Known as Philadelphia TranslocationPresent in 95% of people with CML (Chronic Myelogenous Leukemia)Treated with Tyrosine Kinase Inhibitor - Gleevec (Imatinib)





Gleevec has Almost Doubled the Five Year Survival Rate of CML Patients

Other Signaling Considerations

Other Signaling Considerations

Steroid Hormone Signaling Uses Intracellular, Non-membrane Receptors Steroid Hormone Receptors Act as Transcription Factors When Bound to Hormone Non-hormone Signaling Includes Nerve Transmission and Prostanoid Signaling Src Proteins

are Tyrosine Kinases Found in Various Cell Locations Nerve Transmission Involves Action Potentials Generated by Ion Gradient Changes Oncogenes Cause Cancer and are Mutated Proto-Oncogenes Mutations in Signaling Systems Can Lead to Tumor Formation RAS Mutations that Inhibit GTPase Can Cause Cancer Mutated RAS Most Common Point Mutation in Cancer Phosphorylation of Src’s Tyrosines Turns it OFF Phosphorylated Tyrosines Block Access to Src’s SH2 Domain Src’s SH2 Domain Controls Access to Other Signaling Proteins Mutations Changing Src’s Tyrosines Leave the Protein Always Activated Human EGFR (HER2) HER2 Doesn’t Require EGF Binding for Dimerization/Activation Overexpression of HER2 Linked to Many Cancers HER2 Cancers Treated with Herceptin bcr-abl Fusion links the Tyrosine Kinase of abl with N-terminus & Transcription Control of bcr bcr-abl Fusions Implicated in Many CMLs bcr-abl Tumors Fought with Tyrosine Kinase Inhibitor - Gleevec

Metabolic Melody

Metabolic Melody

Student Nightmares (To the tune of “Norwegian Wood”)

Copyright © Kevin Ahern

http://www.davincipress.com/professional.html

Student Nightmares (To the tune of “Norwegian Wood”)

Copyright © Kevin Ahern

I answered 3 ‘b’. But then I thought. It might be ‘c’

Or was the false true? I can’t undo. It makes me blue

It asked me to list all the enzymes that regulate fat

As I wrote them down I discovered I didn’t know Jack

I ought to give thanks, Scoring some points, filling in blanks

I squirmed in my seat Feeling the heat, shuffling my feet

Professor then told me there wasn’t a chance I would pass

So I started crying and fell through a big pane of glass

I suffered no harm, 'Cuz I awoke, to my alarm

Oh nothing compares To deadly scares, of student nightmares

http://www.davincipress.com/professional.html

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