hormones and signal transduction iii - oregon state...
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EGFR Signaling, Part 1Epidermal Growth Factor Receptor (EGFR)
EGFR Dimer
RTKs -‐ Epidermal Growth Factor
EGFR Signaling, Part 1Epidermal Growth Factor Receptor (EGFR)
EGFR Dimer
Autophosphorylated Tyrosines in
Cytoplasmic Domain
RTKs -‐ Epidermal Growth Factor
EGFR Signaling, Part 1Epidermal Growth Factor Receptor (EGFR)
EGFR Dimer
Autophosphorylated Tyrosines in
Cytoplasmic Domain
Signaling Complex Assembled on
Phosphotyrosines
RTKs -‐ Epidermal Growth Factor
EGFR Signaling, Part 1Epidermal Growth Factor Receptor (EGFR)
EGFR Dimer
Autophosphorylated Tyrosines in
Cytoplasmic Domain
Signaling Complex Assembled on
Phosphotyrosines
GTP GDP
RTKs -‐ Epidermal Growth Factor
EGFR Signaling, Part 1Epidermal Growth Factor Receptor (EGFR)
EGFR Dimer
Autophosphorylated Tyrosines in
Cytoplasmic Domain
Signaling Complex Assembled on
Phosphotyrosines
GTP GDP
GTP
RTKs -‐ Epidermal Growth Factor
EGFR Signaling, Part 1Epidermal Growth Factor Receptor (EGFR)
EGFR Dimer
Autophosphorylated Tyrosines in
Cytoplasmic Domain
Signaling Complex Assembled on
Phosphotyrosines
GTP GDP
GTP
Prepares Cell for Division
RTKs -‐ Epidermal Growth Factor
RAS Activates RAF Kinase
RAF/RAS Activates MEK Kinase
MEK Activates MAP Kinase Cascade
RTKs -‐ Epidermal Growth Factor
RAS Activates RAF Kinase
RAF/RAS Activates MEK Kinase
Transcription Factor Phosphorylation
Activates Gene Expression
MEK Activates MAP Kinase Cascade
RTKs -‐ Epidermal Growth Factor
RAS
RAS is a Family of Related ProteinsEach is Monomeric and like the α-subunit of G-ProteinsRAS Proteins Bind Guanine Nucleotides
RAS
RAS is a Family of Related ProteinsEach is Monomeric and like the α-subunit of G-ProteinsRAS Proteins Bind Guanine Nucleotides
Human r-RAS
RAS
RAS is a Family of Related ProteinsEach is Monomeric and like the α-subunit of G-ProteinsRAS Proteins Bind Guanine Nucleotides
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
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 Hormones Control Metabolism, Inflammation, Immune Functions, Water/salt Balance,Sexual Characteristics, and Response to Illness/Injury
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 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 ReceptorsFive Classes of Steroid Hormones in Two Groups - Corticosteroids and Sex Hormones
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 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 Signaling
Steroid Hormone Signaling
Steroid Hormone Released into BloodCrosses Lipid Bilayer of Target CellBinds to Internal Receptor
Steroid Hormone Signaling
Steroid Hormone Released into BloodCrosses Lipid Bilayer of Target CellBinds to Internal ReceptorInternal Receptor Changes Shape,
Becoming Transcription Factor
Steroid Hormone Signaling
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
Lipid Bilayer
1
1. Hormone Arrives in Blood Receptor Bound to Hsp70
Steroid Hormone Signaling
Cell
Nucleus
Lipid Bilayer
1
1. Hormone Arrives in Blood2
2. Movement Across Lipid Bilayer
Receptor Bound to Hsp70
Steroid Hormone Signaling
Cell
Nucleus
Lipid Bilayer
1
1. Hormone Arrives in Blood2
2. Movement Across Lipid Bilayer
3
3. Hormone Binds Receptor, Hsp70
Released
Receptor Bound to Hsp70
Steroid Hormone Signaling
Cell
Nucleus
Lipid Bilayer
1
1. Hormone Arrives in Blood2
2. Movement Across Lipid Bilayer
3
3. Hormone Binds Receptor, Hsp70
Released
4
4. Movement of Hormone-bound
Receptor to Nucleus
Receptor Bound to Hsp70
Steroid Hormone Signaling
Cell
Nucleus
Lipid Bilayer
1
1. Hormone Arrives in Blood2
2. Movement Across Lipid Bilayer
3
3. Hormone Binds Receptor, Hsp70
Released
4
4. Movement of Hormone-bound
Receptor to Nucleus
5. Transcription
5. Hormone-bound Receptor Binds DNA, Initiates Transcription
Receptor Bound to Hsp70
Steroid Hormone Signaling
Steroid Hormone Signaling
Glucocorticoid Hormone Signaling
Hormone EntryHSP Release
Dimerization Movement to Nucleus
Steroid Hormone Signaling
Glucocorticoid Hormone Signaling
Hormone EntryHSP Release
Dimerization Movement to Nucleus
Transcription Activation
Hormones and Signal Transduction• Non-Hormone Signaling
Cells Communicate in Other Ways Than With Hormones
Hormones and Signal Transduction• Non-Hormone Signaling
Cells Communicate in Other Ways Than With HormonesNerve Transmission
Hormones and Signal Transduction• Non-Hormone Signaling
Cells Communicate in Other Ways Than With HormonesNerve Transmission
Relies on Ion Gradients and Neurotransmitter Molecules to Transmit Signal
Hormones and Signal Transduction• Non-Hormone Signaling
Cells Communicate in Other Ways Than With HormonesNerve Transmission
Relies on Ion Gradients and Neurotransmitter Molecules to Transmit SignalBlocked by Ion Channel Blocking Molecules
Hormones and Signal Transduction• Non-Hormone Signaling
Cells Communicate in Other Ways Than With HormonesNerve Transmission
Relies on Ion Gradients and Neurotransmitter Molecules to Transmit SignalBlocked by Ion Channel Blocking Molecules
Prostanoids
Hormones and Signal Transduction• Non-Hormone Signaling
Cells Communicate in Other Ways Than With HormonesNerve Transmission
Relies on Ion Gradients and Neurotransmitter Molecules to Transmit SignalBlocked by Ion Channel Blocking Molecules
Prostanoids Derived from Arachidonic Acid and Exert Effects Near Where They are Released - Prostaglandins, Prostacyclin and Thromboxanes
Prostaglandin H2 Thromboxane A2
Hormones and Signal Transduction• Non-Hormone Signaling
Cells Communicate in Other Ways Than With HormonesNerve Transmission
Relies on Ion Gradients and Neurotransmitter Molecules to Transmit SignalBlocked by Ion Channel Blocking Molecules
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 Gone Wild• Signaling Gone Wild
Signaling Proteins Play Important Roles in Growth and DivisionOncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled Growth
Signaling Gone Wild• Signaling Gone Wild
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 Gone Wild• Signaling Gone Wild
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 Gone Wild• Signaling Gone Wild
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
Signaling Gone Wild• Signaling Gone Wild
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
Signaling Gone Wild• Signaling Gone Wild
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/FunctionMutations Affecting Expression of Protein
Signaling Gone Wild• Signaling Gone Wild
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/FunctionMutations Affecting Expression of ProteinOther Mutations
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
RAS
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
RAS1. GDP Bound RAS Inactive
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
RAS1. GDP Bound RAS Inactive
2. GTP Binding Activates
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
RAS1. GDP Bound RAS Inactive
2. GTP Binding Activates
3. GTPase Converts GTP to GDP, Inactivating
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
RAS1. GDP Bound RAS Inactive
2. GTP Binding Activates
3. GTPase Converts GTP to GDP, Inactivating4. Mutations of Amino Acids 11/12 or 61 Inhibit GTPase & Activate RAS
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
RAS1. GDP Bound RAS Inactive
2. GTP Binding Activates
3. GTPase Converts GTP to GDP, Inactivating4. Mutations of Amino Acids 11/12 or 61 Inhibit GTPase & Activate RAS5. Activated RAS Stimulates Cell Division
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
RAS1. GDP Bound RAS Inactive
2. GTP Binding Activates
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
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
RAS1. GDP Bound RAS Inactive
2. GTP Binding Activates
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 in 90% of Pancreatic Cancer and 20% of all Cancers
Hormones and Signal Transduction• Signaling Gone Wild
Not All Tyrosine Kinases are RTKsSrc Proteins are Tyrosine Kinases Found in Various
Cell Locations
Src
Hormones and Signal Transduction• Signaling Gone Wild
Not All Tyrosine Kinases are RTKsSrc Proteins are Tyrosine Kinases Found in Various
Cell LocationsDephosphorylated Src Acts to Stimulate Cell Division
Src
Hormones and Signal Transduction• Signaling Gone Wild
Not All Tyrosine Kinases are RTKsSrc Proteins are Tyrosine Kinases Found in Various
Cell LocationsDephosphorylated Src Acts to Stimulate Cell DivisionPhosphorylation of Src’s Tyrosines Turns it OFF
Src
Hormones and Signal Transduction• Signaling Gone Wild
Not All Tyrosine Kinases are RTKsSrc Proteins are Tyrosine Kinases Found in Various
Cell LocationsDephosphorylated Src Acts to Stimulate Cell DivisionPhosphorylation of Src’s Tyrosines Turns it OFFMutations that Affect Src’s Phosphorylation Convert
Src
Hormones and Signal Transduction• Signaling Gone Wild
Not All Tyrosine Kinases are RTKsSrc Proteins are Tyrosine Kinases Found in Various
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
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
Src
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
Src
Src
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
Src
SrcPhosphorylated Tyrosines Block Access to its SH2 Domain and Prevent it From Participating in Signaling Leaving it Inactive
Hormones and Signal Transduction• Signaling Gone Wild
Mutations Affecting Protein Structure/Function
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
Hormones and Signal Transduction• Introduction
HER2-Herceptin Complex
HER2 Doesn’t Require EGF Binding for Dimerization/Activation
Mutations Affecting Expression of Protein
Hormones and Signal Transduction• Introduction
HER2-Herceptin Complex
HER2 Doesn’t Require EGF Binding for Dimerization/ActivationIs Always Signaling Cell to Divide When Dimerized
Mutations Affecting Expression of Protein
Hormones and Signal Transduction• Introduction
HER2-Herceptin Complex
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 Affecting Expression of Protein
Hormones and Signal Transduction• Introduction
HER2-Herceptin Complex
HER2 Doesn’t Require EGF Binding for Dimerization/ActivationIs Always Signaling Cell to Divide When Dimerized
Mutations Increasing Levels of HER2 Found in Several CancersBreast Cancer (15-30%)
Mutations Affecting Expression of Protein
Hormones and Signal Transduction• Introduction
HER2-Herceptin Complex
HER2 Doesn’t Require EGF Binding for Dimerization/ActivationIs Always Signaling Cell to Divide When Dimerized
Mutations Increasing Levels of HER2 Found in Several CancersBreast Cancer (15-30%)
Ovarian Cancer
Mutations Affecting Expression of Protein
Hormones and Signal Transduction• Introduction
HER2-Herceptin Complex
HER2 Doesn’t Require EGF Binding for Dimerization/ActivationIs Always Signaling Cell to Divide When Dimerized
Mutations Increasing Levels of HER2 Found in Several CancersBreast Cancer (15-30%)
Ovarian CancerStomach Cancer
Mutations Affecting Expression of Protein
Hormones and Signal Transduction• Introduction
HER2-Herceptin Complex
HER2 Doesn’t Require EGF Binding for Dimerization/ActivationIs Always Signaling Cell to Divide When Dimerized
Mutations Increasing Levels of HER2 Found in Several CancersBreast Cancer (15-30%)
Ovarian CancerStomach CancerUterine Cancer
Mutations Affecting Expression of Protein
Hormones and Signal Transduction• Introduction
HER2-Herceptin Complex
HER2 Doesn’t Require EGF Binding for Dimerization/ActivationIs Always Signaling Cell to Divide When Dimerized
Mutations Increasing Levels of HER2 Found in Several CancersBreast Cancer (15-30%)
Ovarian CancerStomach CancerUterine Cancer
Treated with Monoclonal Antibody - Herceptin
Mutations Affecting Expression of Protein
Hormones and Signal Transduction• Introduction
HER2-Herceptin Complex
HER2 Doesn’t Require EGF Binding for Dimerization/ActivationIs Always Signaling Cell to Divide When Dimerized
Mutations Increasing Levels of HER2 Found in Several CancersBreast Cancer (15-30%)
Ovarian CancerStomach CancerUterine Cancer
Treated with Monoclonal Antibody - HerceptinHerceptin Binds HER2’s Extracellular Domain to Prevent Dimerization
Mutations Affecting Expression of Protein
Hormones and Signal Transduction• Introduction
Other Mutations
Bcr-Abl Fusion
Chromosomes 9 & 22
abl
bcr
22
9
Hormones and Signal Transduction• Introduction
Other Mutations
Bcr-Abl Fusion
Chromosomes 9 & 22
abl
bcr
22
9
Crossover
Hormones and Signal Transduction• Introduction
Other Mutations
Bcr-Abl Fusion
Chromosomes 9 & 22
abl
bcr
22
9
Fusion Chromosomes
9/22
22/9
bcr-abl fusion
Hormones and Signal Transduction• Introduction
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
Hormones and Signal Transduction• Introduction
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
Hormones and Signal Transduction• Introduction
Bcr-Abl FusionAlso Known as Philadelphia Translocation
Hormones and Signal Transduction• Introduction
Bcr-Abl FusionAlso Known as Philadelphia TranslocationPresent in 95% of people with CML (Chronic Myelogenous Leukemia)
Hormones and Signal Transduction• Introduction
Bcr-Abl FusionAlso Known as Philadelphia TranslocationPresent in 95% of people with CML (Chronic Myelogenous Leukemia)Treated with Tyrosine Kinase Inhibitor - Gleevec (Imatinib)
Hormones and Signal Transduction• Introduction
Bcr-Abl FusionAlso Known as Philadelphia TranslocationPresent in 95% of people with CML (Chronic Myelogenous Leukemia)Treated with Tyrosine Kinase Inhibitor - Gleevec (Imatinib)
Hormones and Signal Transduction• Introduction
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
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
Student Nightmares (To the tune of “Norwegian Wood”)
Copyright © Kevin Ahern
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
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