Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

BIOCHEM Unit 2 > Lecture 12 Catalytic Steroid Hormone Signaling > Flashcards

Lecture 12 Catalytic Steroid Hormone Signaling Flashcards

1
Q

How can we instruct the cell to initiate a specific
transcriptional program?

A

Cellular signaling or signal transduction pathways

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Mechanisms that control catalytic and steroid hormone receptor signaling

A
  1. Receptor tyrosine kinases signaling
  2. Non-receptor tyrosine kinase signaling
  3. STAT protein signaling
  4. Insulin signaling
  5. Nuclear receptor signaling
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Basic Steps in Cell Signal/Transduct Pathways

A
  1. Extracell stim
  2. Extracell Receptor Domain
  3. Intracell Receptor Domain
  4. Signaling Mediators
  5. Transcriptional Response
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Catalytic receptors: Receptor tyrosine kinases (RTKs)

A

Kinases

Phosphatases

ATPases and GTPases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Kinases

A
  1. Phosphorylate substrates (Ser/Thr/Tyr)
  2. Use ATP and produce ADP
  3. Add a phosphate group to a substrate protein
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Phosphatases

A

Remove a phosphate group from a substrate protein

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

ATPases and GTPases

A

Hydrolyze ATP or GTP
And produce ADP or GDP and (Pi)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Receptor tyrosine kinases: Structure

A
  1. Extracellular N-terminal:
    * Ligand-binding region
  2. Transmembrane domain:
    * Hydrophobic domain that traverses the membrane
  3. Intracellular C-terminal domain:
    * Tyr kinase catalytic domain
    * “Dormant” tyrosine kinase activity
    * “Effector” domain
  4. Receptor Activation:
    * Ligand binding
    * Dimerization
    * Activation of the “dormant” Tyr
    kinase activity
    * Adaptor proteins recognize phospho-tyrosine residues, amplify and transduce the signal
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Receptor tyrosine kinases: Activation

A
  1. Growth factor or hormone binds to the extracellular portions of receptor chains.
  2. Tyrosine kinase domains of each chain activate each other.
  3. Tyrosine residues on opposite chains serve as substrates for each of the tyrosine kinase domains. As a consequence, phosphorylated tyrosine residues are present on each of the receptor cytoplasmic tails.
  4. SH2-containing adaptor proteins dock with phosphotyrosines on the cytoplasmic tails of the receptor chains.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Tyrosine residues on opposite chains serve as substrates for each of the tyrosine kinase domains. As a consequence, phosphorylated tyrosine residues are present on each of the receptor cytoplasmic tails.

A
  1. Ligand binding and dimerization
  2. Auto-phosphorylation:
    * The receptor phosphorylates itself
  3. Cross-phosphorylation:
    * The receptor phosphorylate its
    dimerization partner
    * Phospho-tyrosine
  4. Phospho-Tyrosine becomes a “docking site” for
    adaptor proteins
    * Adaptor proteins recognize phospho-tyrosine
    residues (SH2 domain), amplify and transduce the
    signal
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

RTK: Adaptor Proteins

A
  1. Adaptor proteins:
    * Recognize a specific motif, in this case phosphorylated tyrosine residues
  2. Src Homology domains (SH domains)
    * Proteins have SH domains within their structures
    * SH domains exist in many proteins
  3. SH1 domain
    * Tyrosine kinase catalytic domain
  4. SH2 domain
    * Recognizes and binds to phosphorylated-tyrosine residues
  5. SH3 domain
    * Often binds to proteins with SH2 domains bound to phosphorylated tyrosine residues. Recognition domain is associated with poly-proline region.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

SRC Kinases

A

3 domains

SH2 and SH3 mediate protein to protein interactions

SH1 is catalytic domain

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Receptor tyrosine kinases (RTKs)

A

Serve as an “ON/OFF switch”
* Phosphorylate specifically Tyrosine residues
* Fleeting modification
* Possess a “dormant” Tyr kinase
* less common, but very important
* Many are growth factors, and thus can be ONCOGENIC!

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Examples of RTK

A

Insulin receptor,
Transforming Growth Factor
(TGF)
Epidermal Growth Factor (EGF) Platelet Derived Growth Factor (PDGF)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Ras signaling (Ras)

A
  • Oncogene (Rat Sarcoma virus)
  • Small GTP-binding protein
  • Membrane-bound
  • Highly mutated in cancers
    (“always ON” GTP-bound
    mutations)
  • Very important oncogene!
    Mutated in ~25% tumors
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Ras activation

A
  • Active (GTP-bound)
  • Inactive (GDP-bound)
  • Requires a GEF to exchange GDP
    for GTP and become active
  • Requires a GTPase activating
    protein (GAP) to hydrolyze GTP
    and become inactive
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Ras Signaling

A
  1. Ras is membrane-bound and
    GDP-bound (inactive)
  2. Upon RTK activation, Grb2
    (SH2-domain) binds to the
    activated RTK
  3. SOS (GEF) binds Grb2
    (through SH3)
  4. GDP-Ras (inactive) binds to
    Grb2-SOS complex and GDP
    for GTP exchange occurs
  5. GTP-Ras (active) binds to and
    activates the Raf kinase

6.This kinase cascade results in
MAPK (ERK) phosphorylation
and translocation into the
nucleus for transcriptional
activation of cell proliferation
signal.

18
Q

Adaptor proteins: STATs

A

Signal Transducers and
Activators of Transcription

  • SH2 domain-containing protein
  • STATs are also substrates for the RTKs
  • Tyr-phosphorylated STATs dimerize and translocate into the nucleus where they act as transcription factors
19
Q

Adaptor proteins: PI3 kinases

A

Phosphatidylinositol 3 kinase

  • SH2 and SH3 domain-containing protein
  • Phosphorylate membrane inositol
    phospholipids
  • PIP3 a docking site for other signaling molecules (AKT kinase)
  • Signal cell growth and
    survival and are associated with
    cancers!
20
Q

What counteracts most effects of kinases?

A

Phosphatases

Ex. PTEN

21
Q

Bad

A

induces cell death, but phospho-Bad is inactive, thus promoting cell survival! PTEN induces
cell death by disrupting the inactivation of Bad!

PTEN: pot target in prostate cancer

22
Q

Non-receptor tyrosine kinases

A

Some receptors do not possess their own RTK activity

  • Receptors without intrinsic tyrosine kinase activity associate with cytoplasmic non-RTKs, which phosphorylate tyrosine residues on their cytoplasmic tail

Includes:
1. Src non-receptor Tyrosine Kinase
2. Janus Kinases (JAKs)

23
Q

Src non-receptor Tyrosine Kinase

A
  • First non-receptor Tyrosine Kinase discovered
  • At least 8 members of the family
24
Q

Janus Kinases (JAKs)

A
  • “Dormant” cytoplasmic tyrosine kinases
  • Activated by certain hormones & cytokines
  • JAKs phosphorylate Tyr residues the intracellular regions of receptors,
    where SH2 domain-containing proteins bind
  • STATs bind these phospho-tyrosine residues and become themselves phosphorylated by JAKs
    (JAK-STAT pathway)
25
Q

JAK-STAT pathway

A
  1. Ligand binds and causes receptor dimerization.
  2. JAKs phosphorylate tyrosines on the receptor.
  3. SH2 STATs bind to phosphorylated tyrosines, and JAKs phosphorylate STATs.
  4. Phosphorylated STATs dimerize, move to the nucleus, and activate gene transcription.
26
Q

Diabetes Mellitus (DM)

A

Hyperglycemia (>126 mg/dL FBG)

Type I: doesn’t produce insulin
Type II: develop insulin resistance

Hormones that control glucose homeostasis:
* Insulin
* Glucagon

27
Q

Consequences of uncontrolled diabetes

A
  • Neuropathy (nerve damage)
  • Retinopathy (blindness)
  • Circulation problems (limb amputations)
  • Nephropathy (kidney damage)
  • Cardiovascular disease
  • Stroke
28
Q

RTK: Insulin receptor

A
  1. Most-studied RTK with multiple polypeptides.
  2. Protein chains linked before ligand binding.
  3. Insulin binding activates RTK and receptor/IRS phosphorylation.
  4. IRS proteins activate Ras, STATs, and PI3K pathways.
  5. Tissue-specific IRS expression directs specific transcriptional responses.
29
Q

Catalytic receptor signaling

Summary

A
  1. Most receptors are single-chain proteins that dimerize when ligands bind.
  2. Dimerization triggers auto- and cross-phosphorylation on tyrosines.
  3. Phosphorylated tyrosines act as docking sites for SH2 proteins.
  4. Some receptors lack RTK activity but activate other tyrosine kinases (e.g., Src, JAK).
  5. These receptors rely on cytoplasmic kinases to phosphorylate their tyrosines.
30
Q

Steroid receptor (or nuclear receptor) signaling

A

Steroid hormone receptors (Nuclear Receptors):

Act as ligand-activated transcription factors!!!

Hormones derived from cholesterol

Typical NR signaling/effects takes from hours (in cell) to days (in tissue)

These receptors are intracellular!!

31
Q

Steroid Signaling

A

Classical Signaling—-> Nuclear Initiated Steroid Signaling (NISS)

Rapid Signaling —–> Member Initiated Steroid Signaling

32
Q

Type I Receptors

A

Recruit transcriptional activators upon ligand binding

Sex Hormone Receptor
(andro,estro, proges)
Glucocorticoid Receptor
Mineralcorticoid Receptor

33
Q

Type II Receptors

A

Are in a complex with transcriptional
repressors and upon ligand binding, they interact with transcriptional activators

Vitamin A
Vitamin D
Retinoid
Thyroid Hormone Receptor

34
Q

Steroid hormones

A

Derived from cholesterol
Pass through membranes

  1. Cortisol:
    * Stress hormone
    * In adrenal cortex
    * Induces gluconeogenesis
  2. Estrogens
    * Female sex hormone
    * In ovaries
    * Controls menstrual cycle and
    female secondary sexual
    characteristics
  3. Androgens
    * Male sex hormone
    * In testes
    * Controls male secondary sexual
    characteristics and anabolism
35
Q

Steroid Hormone Receptors (NRs) Structure

A

*Transactivation domain:
Gene regulatory domain that interacts with transcriptional co-activators or co-repressors

  • DNA binding domain:
    Region of the receptor that interacts with DNA sequences (HREs)
  • Ligand binding domain:
    Region of the receptor that interacts with a given hormone
  • Ligand binding induces a conformational change in the
    NR that stimulates its translocation to the nucleus and binding to HRE to act as a transcription factor
36
Q

Steroid Hormone Receptors
(NRs) Signaling:

A
  1. Ligand binds in the cytoplasm.
  2. Receptor moves to the nucleus.
  3. Receptor-ligand complex binds to HREs on DNA.
  4. Complex recruits co-activators or repressors to control transcription.
  5. Receptors can be nuclear or cytoplasmic (all intracellular).
  6. Some receptors repress but activate transcription when bound by ligand (Type II).
37
Q

Steroid Receptor Signaling

A
  1. Cortisol binds to its receptor: When cortisol (a steroid hormone) binds to the glucocorticoid receptor (GR), it changes the shape of the receptor.
  2. GR dimerization and interaction with DNA: The receptor forms a dimer (pairs up) and moves to the nucleus, where it binds to specific DNA sequences called glucocorticoid response elements (GRE).
  3. Gene transcription begins:
    The receptor recruits coactivators to the basal transcription complex, which helps start the transcription of target genes, leading to gene expression.
38
Q

Two types of steroid signaling

A

Classical/Nuclear-Initiated Steroid Signaling (NISS):
Steroid binds to its receptor in the cytoplasm and affects gene transcription over hours or days.

Membrane-Initiated Steroid Signaling (MISS):
Steroids act rapidly (seconds or minutes) via receptors on the membrane.

39
Q

Membrane-initiated signaling

A

The steroid receptor on the membrane interacts with other proteins, such as kinases (e.g., Src, Ras), to activate signaling pathways quickly.

40
Q

Medical applications of steroid hormone signaling

Estrogen

A

Estrogen-dependent Breast
Cancer:
* Breast cancers require ER signaling in order to grow
* Receptor antagonists inhibit
growth
* Tamoxifen is drug (ER antagonist) used against types of breast cancers
5 years

41
Q

Medical applications of steroid hormone signaling

Androgen

A

Prostate cancers require AR
signaling in order to grow

  • Receptor antagonists can inhibit
    growth
  • Flutamide is drug (AR antagonist) used against prostate cancers
  • PSA (Prostate Specific Antigen)
    test: The PSA gene is regulated by
    AR and elevated levels suggest
    increased prostate growth
    signaling!

BIOCHEM Unit 2 (2 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions