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ADV Cell Bio > Chapter 4 > Flashcards

Chapter 4 Flashcards

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Biology 101 flashcards
1
Q

Initiation of cell division

A

typically signals from outside the cell signals cell division

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2
Q

Initiation of cell division
Transduction of growth signaling involves:

A
  • Growth factors
  • growth factor receptors
  • Intracellular signal transducers
  • Nuclear transcription
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3
Q

Growth Factor Receptors

A
  • Growth factor receptors (GFRs) link signals outside the cell to intracellular regions
  • Many GFRs are kinases
    -gamma phosphate transferred from ATP/GTP to hydroxyl groups of specific aa in target protein
    -Tyrosine or serine/threonine
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4
Q

Epidermal growth factor signaling

A
  • Signaling through (EGF) is widely studied in cancer
  • EGF family: family of tyrosine kinases that respond to EGF
    • 4 members:
      • EGFR; ErbB1; HER1
      • ErbB2; HER2; HER2/neu
      • ErbB3; HER3
      • ErbB4; HER4
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5
Q

Steps of EGF Signaling

A
  1. Growth factor binds to receptor
  2. Receptor dimerizes
  3. Autophosphorylation
  4. Activation of intracellular transducers
  5. Activation of ser/thr kinase cascade
  6. Regulation of transcription factors for gene expression
    10
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6
Q

Step 1
EGF binds to receptor

A

the extracellular domains of EGFR form a binding pocket that allows for EGF binding

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7
Q

Step 2
EGFR Dimerizes

A

-EGF binding to the EGFR causes conformational change that reveals dimerization domain
-Facilitates binding to another, similar domain after that receptor has also bound to EGF.
-Can homodimerize or heterodimerize

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8
Q

Step 3
Autophosphorylation

A

Conformational change after ligand disrupts intramolecular autoinhibitory interactions
- Result is kinase activation: ATP and substrate can now access the cytoplasmic catalytic kinase domain
- Kinase domain of one receptor
phosphorylates others at multiple
tyrosines and vice versa
- Phosphorylation necessary for
recruiting substrate proteins

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9
Q

Step 3: Autophosphorylation
Kinase activity must be turned off at a certain time:

A
  • Additional phosphorylation triggers conformational change to inhibit ligand binding/kinase activity
  • Desphosphororylation by tyrosine phosphatases
  • Kinase domain bound by negative regulators
  • Receptor endocytosis and degradation
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10
Q

Step 4
Activation of Intracellular Transducers

A

Some phosphorylated tyrosine residues create high-affinity binding sites for proteins with Src homology domains
- SH2: 100 aas long, recognizes and binds sequences C-terminal to phosphorylated tyrosines
- SH3: 50 aas long, bind to residues on partner proteins.
- E.g., Grb2 - 1 SH2 and SH3 domains

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11
Q

Grb2
SOS
RAS proteins

A

Grb2: 1 SH2 and 2 SH3 domains
- SH3s interact with SOS
SOS: a guanine nucleotide exchange factor that activates RAS
Ras proteins: GTP-binding proteins that can activate ser/thr kinases
- N-RAS, H-RAS, and K-RAS
- Farnesylation directs RAS to the cell membrane
- Inactivate when bound to GDP
- Active when bound to GTP- can now interact with downstream proteins
-E.G., activates ser/thr kinase raf

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12
Q

Step 4
GTPase activating proteins (GAPs)

A

Catalyze hydrolysis of GTP to GDP to terminate signal
- RAS proteins have intrinsic GTPase activity for self-regulation

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13
Q

Step 5
Activation of Ser/Thr cascade

A

Raf: ser/thr kinase activated by RAS; carries signal away from membrane; phosphorylates MEK
- aka MAPKKK
MEK: tyrosine and ser/thr kinase that phosphorylates MAPK
- aka MAPKK
MAPK (mitogen-activated protein kinase): family of ser/thr kinases
- Phosphorylate transcription factors to regulate their activity

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14
Q

Step 6
Regulation of Transcription Factors

A

MAPKs regulate many transcription factors
-Example:
- AP-1 transcription factors–involved in growth, differentiation and death
-Phosphorylation of Fos alters DNA-
binding activity
- Myc family of transcription factors – regulate expression of genes important for proliferation
- Target N-ras and p53

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15
Q

More than regulating Gene expression..

A

Cell signaling can also affect cell behavior
-Src: intracellular tyrosine kinase with SH2 and SH3 domains
- activated EGFR interacts with SH2 domain of SRC to induce cell proliferation
- Focal adhesion kinase (FAK) also interacts with SH2 - important for cell shape, adherence, and motility

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16
Q

Oncogenes

A

(mutated gene whose protein product is produced in higher quantities/has increased activity)
Over 11 oncogenes and 15 tumor suppressors identified
- Examples seen in every type of protein involved in growth factor signaling pathways
(ecDNA is less compact/more accessible

17
Q

Historical Data

A

-Discovery of oncogenes came from studies of retroviruses
-Retroviruses inject RNA into host
- End up with a provirus: DNA form a retrovirus that results from reverse transcription
-Integrated randomly into host genome
-Replicated, transcribed, and
translated by the host.
- Translocation of viral RNA
produces viral proteins needed for
synthesis of new viral particles
- Virus can acquire fragments of
genes from host at sites of
integration
-E.g., Rous Sarcoma virus acquired truncated form of c-src

18
Q

Historical data
(next slide)

A

Rous (1991) - Rous Sarcoma Viruse and v-scr viral

Bishop and Varmus (1976) - c-src (normal cellular)

19
Q

Growth Factors as Oncogenes

A

Platelet-derived growth factor (PDGF): stimulates epithelial cells around wound edge to proliferate and repair damage
- One of the first identified proto-oncogenes
- Oncogene results in cytoplasmic rather than secreted PDGF
-Result: PDGF signaling inappropriately
activated, leading to unregulated
growth

20
Q

Growth Factors as Oncogenes
slide 2

A
  • EGFR is a proto-oncogene
  • EGFR oncogene is a truncated form of EGFR - doesn’t have an extracellular domain
    • Result is constitutive activation
  • Oncogenic activation of receptor tyrosine kinases occurs through mutations that cause:
    • Constitutive tyrosine activation
    • Dimerization
    • Altered substrate activity
21
Q

Intracellular Signal Transducers as Oncogenes

A
  • Rasis most commonly mutated oncogene
    -Mutations result in loss of GTPase activity of RAS protein
    • So, RAS-GTP can’t be inactivated to
      RAS-GDP
      -Result: constitutive activation of RAs
      protein
  • B-Raf point mutation common in melanoma
    -Result: constitutive kinase activity, I.
    insensitivity to feedback mechanisms
22
Q

Intracellular Signal Transducers as Oncogenes
ABL

A
  • ABL: Nuclear threonine kinase involved in DNA damage-induced apoptosis
  • Translocation places in next to bcr
    -BCR-ABL fusion protein maintained in
    cytoplasm
    -Result: kinase activity constitutively
    active in cytoplasm - access to
    different substrates
23
Q

Transcription Factors as Oncogenes

A
  • AP-1 components (Jun and Fos) are proto-oncogenes
  • Mutation of fos results in truncation and eliminates a motif involved in mRNA instability
    • Result: mRNA with a longer half-life, ultimately leading to inappropriate increase in transcription of AP-1 regulated genes
24
Q

Targeting Kinases

A
  • Structure of catalytic domains of kinases very similar when active
    -but, many specific inhibitors have been created
25
Q

Targeting EGFR

A

Herceptin: humanized monoclonal anibody that binds extracellular domain of ErbB2
- Binding results in:
-increased receptor degradation
-Inhibition of angiogenesis
-Recruitment of immune cells resulting
in cytotoxicity
- Used for treatment of metastatic breast cancers that overexpress ErbB2
Tarceva: directed against tyrosine kinase activity of EGFR family receptors
- compete for binding ATP
- Initial response rate high, but drug resistance common due to additional mutations

26
Q

Targeting BCR-ABL: Gleevec

A
  • 95% of CML patients express BCR-ABL fusion protein
  • Gleevec: binds to ATP-binding pocket of catalytic of ABL
    -Very successful in treatment of early-
    stage CML
    • Mutations lead to relapse
      -Supports the theory of oncogene
      addiction
27
Q

Targeting Ras and Raf

A
  • Ras targeting has not been successful
    -led to Ras being labeled “undruggable”
    -Much research focused on finding a drug
  • Downstream effectors targeted with some success
    -Drug resistance to mutations or switching to different kinase for constitutive growth signals

ADV Cell Bio (6 decks)

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