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BioMedChem M2 > 13 - Enzyme Coupled Reactions > Flashcards

13 - Enzyme Coupled Reactions Flashcards

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1
Q

Photo of typical kinase/phosphorylation cascade

A
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2
Q

Feedback Loops in Signaling

IkB-a / NFkB

A

NEGATIVE FEEDBACK LOOP

  • NFkB PRODUCES IkB-a Gene
  • IkB-a** INHIBITS **NFkB
    • ​​TNF-a signal inhibits -> IkK –//–> IkB-a
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3
Q

Receptor Tyrosine Kinases

RTK

A
  • Signal Molecule = Ligand –> binds to extracellular binding domain
    • ​Dimerization / conformational change
      • -> activate Kinase Domains
      • SH2 domains bind the phosphorylated TYR
  • Autophosphorylation on several TYR residues
    • Phosphoryl groups = Docking Sites
      • ​for <– Intracellular signaling proteins__​​__​​
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4
Q

TOR

A

Type of Ser/Thr Kinase

Along with (PIP3)-PDK, activates AKT

to inhbit apoptosis

  • RAPAMYCIN
    • targets / inhibits TOR
      • which will downregulate AKT, allowing for APOPTOSIS
        • useful in cancer to kill cels
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5
Q

Examples of Receptor Tyrosine Kinases

RTK

A
  • PDGF (​Platelet Derived Growth Factor)
    • split tyrosine kinase domain
    • PI3-kinase / GAP / PLC-gamma
  • Insulin Receptor (IR) / IGF-1 Receptor
    • slightly different, form
      • Disulfide-linked tetrameric complex​
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6
Q

Describe the activity of PI 3-Kinase

A

Produces Lipid Binding Sites for proteins

  • Active RTK -> activate P1 3-Kinase
    • ​adds P to the 3rd position, (both membrane bound)
      • PIP2 –> PIP3
        • PREVENTS PIP2 from being cleaved BY PLC
          • ​into DAG + IP3
  • ​​​PTEN Phosphotase inactivates P1-3K
    • ​dephosphorylation
  • PIP3 = most important docking site__​ in signaling
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7
Q

PDGF Receptor

(Platelet Derived Growth Factor)

A

​Type of RTK-Receptor

  • phosphorylated Tyr-P Docking Sites can activate:
    • GTPases (small monomeric)
      • via GAPs = GTPase - activating protein
    • IP3 & CA2+ signaling
      • via PLC-gamma = phospholipase C
      • SH2 / SH3 domains
    • PIP3 phosphorylation
      • ​via PI3 kinase = regulatory subunit
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8
Q

2 Ways for Signaling Protein Activation

in RTKs

A

Phosphorylation

(auto - by receptor’s kinase or other kinase activity)

Docking

(conformational change)

Phosphoryl groups serve as the docking site for signaling proteins

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9
Q

Receptor Ser/Thr Kinases

Types / Definition

A

Structurally similar to Tyrosine Kinases, form Hetrodimers

FAST ACTING, direct phosphorylate SMADs (transcription factors)

TGF-b superfamily

TNF-a receptor family

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10
Q

TNF-alpha

A

Type of Receptor Ser/Thr Kinase

Innate Immunity / Inflammation / APOPTOSIS

  • TNFa = trimer -> activate IKK complex
    • phosphorylates IkB, to free NFkB
      • allows for transcription of target genes
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11
Q

INSULIN RECEPTOR & IGF1

type of RTK’s

A
  • slightly different RTK
    • undergoes post-ranslational modification
      • –> DISULFIDE linked complex
  • ​​Insulin -> IR (insulin receptor)
    • autophosphorylation -> recruits IRS1
      • P-IRS1 binds PI-3kinase
        • ​trannsduces info to nucleus
          • downstream cascade
          • long response time to complete enzymatic rxn
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12
Q

RAS

Definition / function

H-K-N (genes)

A

_*Small* Monomeric GTP-Binding Protein_ (G-protein)

  • Almost all RTK’s activate RAS
    • LIPID ANCHOR, associated w/ membrane
    • resembles alpha-subunit of trimeric GPCR
    • Activated by RAS-GEF proteins
      • (guanine nucleotide exchange factor = turns ON)
    • Active RAS –> propogates signal
      • often invovled in CELL PROLIFERATION (growth/survival)
        • goes on to activate MAP kinase (cascade)
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13
Q

Drugs that BLOCK JAK-STAT pathway, do what?

tyr-kinase ASSOCIATED Receptors

A

ANTI-INFLAMMATORY

Biologic drugs = Xeljanz / kneret

Cytokine receptors = induce INFLAMMATORY responses

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14
Q

How do enzyme-coupled receptors contribute to

PROGRAMMED CELL DEATH?

A

RTK & TNF-a Receptor= Enzyme coupled receptors

  • RTK -> P1-3K -> PDK1 + mTOR -> activate Akt
    • phosphorylates BAD -> Inhibition of Apoptosis
      • BAD normally inhibits the apoptosis inhibitory protein
  • TNF-a Receptor Trimer(ser/thr-kinase) -> activates IKK
    • ​phosphorylates IKB (inhibits NFkB)
      • –> FREES NFkB which exposes nuclear localization motif
        • transcription of NFkB genes
          • Important in innate immunity / inflammation / APOPTOSIS
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15
Q

How do monomeric G-proteins differ from

GPCR G-Proteins?

A

Ex. Ras / Rho = small monomeric GTP-binding protein/GTPase (G-protein)

  • They relay signals from surface receptors
    • Ras - from RTKs
    • Rho - from surface receptors -> cytoskeleton + etc.
  • GPCR G-proteins:
    • ​are LARGE & hetero trimeric
    • RECEPTOR
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16
Q

JAK-STAT

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A

Type of Tyrosine-Kinase ASSOCIATED Receptor

FAST ACTING ,

STATs bind via SH2 (does not have own domain)

  • Cytokine binds -> dimerization (single pass)
    • JAK trans phosphorylate, STATs bind via SH2
      • STATs dissociate into nucleus
        • target gene transcription
17
Q

What type of signaling cascades do

monomeric G-proteins regulate?

Study These Flashcards
A

Ex. Ras / Rho = small monomeric GTP-binding protein/GTPase (G-protein)

  • RTK -> RAS -> MAP-Kinase (mitogen activaed protein kinase)
    • AMPLIFY SIGNAL
      • ​–> Changes in Protein / Gene activity/expression
    • Often involved in cell proliferation
  • Surface receptor signal -> RHO
    • couples cell-surface receptors to the cytoskeleton
      • modulate cell shape / motility / adhesion / cycle
18
Q

Describe Fundamental Functional Domains

of Enzyme Coupled Receptors

Study These Flashcards
A
  • 2 (3) Domains:
    • Extracellular Ligand-Binding Domain
      • Many respond to Growth Factors
    • ​Single Trans-membrane domain (segment)
    • Cytosolic Domain​​:
      • contains or associates w/ an enzyme​
        • not trimeric G proteins
19
Q

Enzyme Coupled Receptors

Study These Flashcards
A
  • 2 Domains:
    • Extracellular Ligand-Binding Domain
      • Many respond to Growth Factors
    • Cytosolic Domain​​:
      • contains or associates w/ an enzyme
        • ​ex Kinase
          • not trimeric G proteins
  • ​​​Largest class:
    • Receptor Tyrosine Kinases = RTK
20
Q

Describe the activity of PIP3

Study These Flashcards
A

PIP3 = Second messenger, Brings/activates:

PDK1 & AKT inhibits apoptosis

  • RTK->PI 3-K => PIP3 signals:
    • PDK1** + **mTOR
      • _​_phosphorylates & activates _AKT_
    • Active-P-AKT dissociates from membrane
      • phosphorylates BAD (inhibitor of apoptosis INHIBITOR)
        • FREES active apoptosis inhibitory protein
          • ​INHIBITION OF APOPTOSIS
21
Q

MAP Kinase signaling modules

3-component system

Study These Flashcards
A

RAF / MEK / ERK

  • ERK** can **enter the nucleus
  • ALL 3 can be brought together on SCAFFOLDS
22
Q

What types of interaction domains facilitate

signaling complexes?

Study These Flashcards
A

SH2 = SRC homology domains that bind Tyr-P

23
Q

Describe how SIGNALING COMPLEXES develop

24
Q

SH2

SRC Homology domains

Study These Flashcards
A

type of interaction domain

Bind to Tyr-P

commonly seen on RTK’s due to the phos-tyrosine

Interaction domains are diverse and require SOME phosphorylation

25
26
**_Tyrosine-Kinase ASSOCIATED Receptors_** Types & Definition
*don't have their OWN kinase domains,* must associate w/ **other cytoplasmic kinases for active signaling** **_Cytokine Receptors**_ = _**Jak-STAT_** **_Antigen Receptors_** = T-cell/b-cell, work with SRC kinases **_Integrins_** **_TLRs_** = toll-like receptors
27
**RTK's can activate what ?** **via what?**
**_Tyr-P Docking Sites_** *not all recruited proteins relay signals, some **INHIBIT** relays* * After phosphorylation of the Kinase, RTK's activate: * **GTPases** (*small monomeric)* * via **_GAPs_ =** GTPase - activating protein * **IP3 & CA2+** signaling * via **_PLC-gamma_** = phospholipase C * SH2 / SH3 domains * **PIP**3 phosphorylation * **​**via **_PI3 kinase_** = regulatory subunit
28
**Feedback Loop Signaling GRAPH PHOTO**
* LEFT shows: * Release of the Kappa B = Active Kappa B to TRANSCRIBE * TNF pulse -\> Short BUMP of Kappa B (purple) * Gene A expression is expressed (blue) * Right graph: * Longer progression of TNF so more KAPPA B is activated * -\> FEEDBACK LOOP IS SHOWN * -\> KAPPA B is being inhibited by itself (NEGATIVE FEEDBACK) * Gene B and Gene A are both being transcribed
29
**MAP Kinase**
**M**itogen **A**ctivated **P**rotein **K**inase * RTK -\> **RAS** signaling -\> activated MAP Kinase * *since RAS (TYR-P) is short lived, reversed by **phosphatases*** * MAP carries out a **_longer response / AMPLIFY signal_** * by **additional phosphorylation** of the MAP kinase * Amplified signal goes on to: * change **protein activity / gene expression**
30
**_What are functional differences between_** **_RTKs vs Ser/Thr Kinases_** provide examples
* **RTKs** - dimerization ( * **​**very similar to GPCR G-proteins * almost always activate **monomeric GTPases (RAS)** * **​-\> MAP** kinase cascades to **AMPLIFY signals** * **​**can also *inhibit* relays * ***Tyr-Kinase ASSOCIATED Receptors*** *(JAK-STAT)* * *​do **NOT** have their **own kinase domains*** * ***must associate w/ other cytoplasmic kinases** for signaling* * _​**Ser/Thr Kinase Receptors**_ (_TGF-b/a)_ * form **_heterodimers_** (b) / **trimer** (a) * **_FAST acting_** * directly phosphorylate **SMADs** **_(transcription factors)_**
31
**AKT** ***aka PKB (protein kinase B)***
is p-activated by **_(_****_PIP3)_** - **_PDK1_ + _mTOR_** to then dissoociate from membrane --\> **Phosporylate** ***_BAD_*** *frees bad from inhibiting the _apoptosis inhibitory protein_* promotes **_CELL SURVIVAL_** by ***inhibiting apoptosis*** * RTK -\> PI 3-K -\> PIP3 * PIP3 phosphorylates and activates both PDK1 & AKT * TOR = Ser/thr kinase that helps activates AKT
32
**Scaffolds** **Adv / Disadvantages**
_Regulators of ​key SIGNALING Pathways_ **_LOCALIZATION**_​ & _**TETHERING_** *require coordination / all components to come together* * **Interact / Bind** with multiple membbers of a signaling pathways * ex. _MAP kinase_ signaling modules = **Raf / Mek / Erk** * and **tether into a COMPLEX**
33
**TGF-Beta** Transforming Growth Factor B
Type of **_Receptor Ser/Thr Kinases_** **_FAST ACTING_** * TGFB ligand -\> **heterodimeric** receptor * recruits & phosphoralates **SMAD2/3** * Recruits SMAD4 -\> translocates to nucleus * regulate genes
34
**FRET**
_Fluorecense Resonance Energy Test_ * Experiment used to see the * ***SHORT LIVED ACTION OF RAS***​ * uses Fluorecent dye on the GTP
35
**RAS in Cancer**
*Normal Ras = **Proto-Oncogene*** **_Mutant Constitutively active RAS = ONCOGENE_** * Mutations **permenently** activate **RAS** (signals cell growth / survival) * which can lead to **CANCER** * 30% of tumors have hyperactive RAS
36
**What *INACTIVATES* PIP3?**
**_PTEN_** _phosphatase_ ## Footnote *Mutations in **PTEN** prolong signaling and is seen in several cancers​* * ***dephosphorylates** PIP3* * PIP3 is made by PI-3Kinase
37
**Tyrosine Phosphotases vs Ser/Thr Phosphotases**
***_STRUCTRUALLY UNRELATED_*** to one another both are **EQUALLY IMPORTANT** in turning **_OFF SIGNALS_**
38
**How are RAS proteins deactivated?**
**_PHOSPHATASES_** ## Footnote * RAS (TYR-P) is *short lived* * due to _phosphatases_ quickly reversing modification * Avoided/longer response carried out by: * additional phosphorylation of MAP-Kinase
39
**_How do inhibitors of transduction pathways_** **_INDUCE APOPTOSIS?_**
**BAD & IkB** * **BAD** is normally ***inhibiting the apoptosis _INHIBITORY_ protein*** * (DOUBLE *NEGATIVE)* * activated-P-**AKT** phosphorylates **BAD**, * which frees the _apoptosis *inhibitory protein*_ * allows it to ***_Inhibit apoptosis!_*** * **IkB** is normally ***inhibiting NFkB*** * **NFkB** signalling is important in **apoptosis**

BioMedChem M2 (8 decks)

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