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BioMedChem M2 > 13 - Enzyme Coupled Reactions > Flashcards

13 - Enzyme Coupled Reactions Flashcards

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

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?

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

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

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

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

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?

A

SH2 = SRC homology domains that bind Tyr-P

23
Q

Describe how SIGNALING COMPLEXES develop

24
Q

SH2

SRC Homology domains

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

26
Q

Tyrosine-Kinase ASSOCIATED Receptors

Types & Definition

A

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
Q

RTK’s can activate what ?

via what?

A

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
    • PIP3 phosphorylation
      • ​via PI3 kinase = regulatory subunit
28
Q

Feedback Loop Signaling GRAPH PHOTO

A
  • 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
Q

MAP Kinase

A

Mitogen Activated Protein Kinase

  • 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
Q

What are functional differences between

RTKs vs Ser/Thr Kinases

provide examples

A
  • 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
Q

AKT

aka PKB (protein kinase B)

A

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
Q

Scaffolds

Adv / Disadvantages

A

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
Q

TGF-Beta

Transforming Growth Factor B

A

Type of Receptor Ser/Thr Kinases

FAST ACTING

  • TGFB ligand -> heterodimeric receptor
    • recruits & phosphoralates SMAD2/3
      • Recruits SMAD4 -> translocates to nucleus
        • regulate genes
34
Q

FRET

A

Fluorecense Resonance Energy Test

  • Experiment used to see the
  • SHORT LIVED ACTION OF RAS​
  • uses Fluorecent dye on the GTP
35
Q

RAS in Cancer

A

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
Q

What INACTIVATES PIP3?

A

PTEN phosphatase

Mutations in PTEN prolong signaling and is seen in several cancers​

  • dephosphorylates PIP3
    • PIP3 is made by PI-3Kinase
37
Q

Tyrosine Phosphotases vs Ser/Thr Phosphotases

A

STRUCTRUALLY UNRELATED to one another

both are EQUALLY IMPORTANT in turning OFF SIGNALS

38
Q

How are RAS proteins deactivated?

A

PHOSPHATASES

  • RAS (TYR-P) is short lived
    • due to phosphatases quickly reversing modification
  • Avoided/longer response carried out by:
    • additional phosphorylation of MAP-Kinase
39
Q

How do inhibitors of transduction pathways

INDUCE APOPTOSIS?

A

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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