III. Signal transduction and cell cycle | 42. Phosphatidylinositol signaling pathways Flashcards

1
Q

I. Basics
1. What are the features of phospholipids?

A
  • The plasma membrane contains phospholipids that are more than just structural.
  • A phospholipid is amphiphilic, which means it has both hydrophobic and hydrophilic region
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2
Q

I. Basics
2. Describe the structure of phospholipids

A

A phospholipid is amphiphilic, which means it has both hydrophobic and hydrophilic region:
- Hydrophilic head: glycerol bound to a negatively charged phosphate group by a phosphate ester bound. The glycerol has 3 carbons, each having one hydroxyl group (-OH) which binds the phosphate and the two fatty acid chains in the tail
- Hydrophobic tails: two fatty acid chains attached to the glycerol by ester bonds

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3
Q

II. Phospholipase
1. What are Phospholipases?

A

Phospholipases are enzymes that hydrolyze phospholipids into fatty acids and phospholipids.

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4
Q

II. Phospholipase
2. What is the target of Phospholipases?

A

The ester bonds between the glycerol and the R groups (phosphate and FAs) are the target of cleavage by different phospholipases.

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5
Q

II. Phospholipase
3. What are 4 examples of phospholipase?

A
  • Phospholipase A1
  • Phospholipase A2
  • Phospholipase C
  • Phospholipase D
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6
Q

II. Phospholipase
4. What is the role of Phospholipase A1?

A

Phospholipase A1 cleaves the 1st ester bond (FA)

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7
Q

II. Phospholipase
5. What is the role of Phospholipase A2?

A

Phospholipase A2 cleaves the 2nd ester bond (FA), side chain R2 usually arachidonic acid

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8
Q

II. Phospholipase
6. What is the role of Phospholipase C?

A

Phospholipase C cleaves the 3rd ester bond to the phosphate group

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9
Q

II. Phospholipase
7. What is the role of Phospholipase D?

A

Phospholipase D cleaves the ester bond between the phosphate and the side chain R3

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10
Q

III. Phospholipase C
1. What are the features of Phospholipase C?

A

Phospholipase C (PLC) in humans (animals) is specific for phosphatidylinositol 4,5-bisphosphate (PIP2), which is a phospholipid with an inositol bound to the phosphate group.

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11
Q

III. Phospholipase C
2. What is the mechanism of Phospholipase C?

A

Activated phospholipase C will cleave PIP2, to generate two 2nd messengers: diacylglycerol (DAG) and inositol-triphosphate (IP3).

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12
Q

III. Phospholipase C
3. Is phospholipase C a family of enzymes?
=> T/F?

A

TRUE!!!

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13
Q

III. Phospholipase C
4. Phospholipase C is a family of enzymes
=> List 3 enzymes with their role

A
  • PLCβ contains a G-protein interaction domain, which will be activated by Gq
  • PLCδ functions in amplifying the signal
  • PLCγ contains SH2 and SH3 domains, meaning it can be activated by receptor tyrosine kinases (e.g. insulin receptor)
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14
Q

IV. IP3 signaling way
1. What is PLC activated by?

A

LC will be activated by a Gq G-protein, which will generate IP3 and DAG from PIP2.

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15
Q

IV. IP3 signaling way
2. What is IP3?

A

IP3 is a water soluble molecule that leaves the plasma membrane and diffuses rapidly through the cytosol.

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16
Q

IV. IP3 signaling way
3. What is the mechanism of IP3?

A
  • IP3 is a water soluble molecule that leaves the plasma membrane and diffuses rapidly through the cytosol.
  • When it reaches the ER, it binds and opens an IP3-gated Ca2+- channel (IP3 receptors) in the ER membrane. Ca2+ stored in the ER is released through the open channels, quickly raising the concentration of Ca2+ in the cytosol.
17
Q

IV. IP3 signaling way
4. What are the location and role of DAG?

A

DAG (=amphiphile – both hydrophilic & hydrophobic properties), which remains embedded in the plasma membrane, will in the presence of Ca2+ activate PKC.

18
Q

IV. IP3 signaling way
5. Describe the structure of PKC?

A

PKC consists of two domains: one regulatory domain (for DAG and Ca2+) and a catalytic domain (for ATP and substrate).

19
Q

IV. IP3 signaling way
6. What is the mechanism of PKC?

A
  • PKC consists of two domains: one regulatory domain (for DAG and Ca2+) and a catalytic domain (for ATP and substrate).
  • When PKC is activated by Ca2+, it is translocated to the plasma membrane where it binds phosphatidyl-serine residues and DAG.
  • This activation causes the PKC to a conformation change and release of an inhibitory molecule.
  • PKC will ‘’open up’’, so that its catalytic site is available to phosphorylate target proteins.
  • PKC will be active for as along as the Ca2+-signal lasts, and will dissociate from the membrane after the activation.
20
Q

IV. IP3 signaling way
7. How is PLCγ activated?

A

PLCγ activated by receptor tyrosine kinases: leading the enzyme to the substrate

21
Q

IV. IP3 signaling way
8. What are the steps in IP3 signaling way?

A
  • IP3 is a water soluble molecule that leaves the plasma membrane and diffuses rapidly through the cytosol.
  • When it reaches the ER, it binds and opens an IP3-gated Ca2+- channel (IP3 receptors) in the ER membrane.
  • Ca2+ stored in the ER is released through the open channels, quickly raising the concentration of Ca2+ in the cytosol.
  • DAG (=amphiphile – both hydrophilic & hydrophobic properties), which remains embedded in the plasma membrane, will in the presence of Ca2+ activate PKC.
  • PKC consists of two domains: one regulatory domain (for DAG and Ca2+) and a catalytic domain (for ATP and substrate).
  • When PKC is activated by Ca2+, it is translocated to the plasma membrane where it binds phosphatidyl-serine residues and DAG.
  • This activation causes the PKC to a conformation change and release of an inhibitory molecule.
  • PKC will ‘’open up’’, so that its catalytic site is available to phosphorylate target proteins.
  • PKC will be active for as along as the Ca2+-signal lasts, and will dissociate form the membrane after the activation.
22
Q

V. Signaling with PI 3-kinase
1. How does it signal with PI 3-kinase?

A
  • Phosphoinositide 3-kinase (PI 3-kinase) is activated in different pathways, such as growth factor, insulin and integrin signaling, and is a part of the survival pathway
  • Mainly phosphatidylinositol 3,4-bisphosphate (PI [3,4]-P2) and phosphatidylinositol 3,4,5-trisphosphate (PI [3,4,5]-P3)
  • The lipid products generated by PI 3-kinase recruit PH domain proteins to the plasma membrane, for example PKB (Akt) and 3-phosphoinositide-dependent protein kinase-1 (PDK1)
23
Q

V. Signaling with PI 3-kinase
2. What are the 3 classes of PI 3-kinase? Describe

A

There are 3 classes of PI 3-kinases, where only class I is involved in signaling:
- Class I.A: contains a 85kDa regulatory subunit which has the SH2 domain that is phosphorylated by receptor tyrosine kinases and a 110kDa catalytic subunit which contains the catalytic domain
- Class I.B: consists of the βγ subunit of heterotrimeric G-proteins and a 110kDa catalytic subunit

24
Q

V. Signaling with PI 3-kinase
3. Describe Class I.A

A

Class I.A: contains a 85kDa regulatory subunit which has the SH2 domain that is
phosphorylated by receptor tyrosine kinases and a 110kDa catalytic subunit which
contains the catalytic domain

25
Q

V. Signaling with PI 3-kinase
4. Describe Class I.B

A

Class I.B: consists of the βγ subunit of heterotrimeric G-proteins and a 110kDa
catalytic subunit

26
Q

V. Signaling with PI 3-kinase
5. How does activation of class I.A work?

A
  • Class I.A PI 3-kinase can bind to an auto-phosphorylated receptor (tyrosine kinase)
    or GTP-bound Ras
  • Concurrent binding results in the strongest activation
27
Q

V. Signaling with PI 3-kinase
6. How does activation of class I.B work?

A

Can be activated by a receptor tyrosine kinase, for example insulin receptor

28
Q

V. Signaling with PI 3-kinase
7. What is the mechanism for the Activation of the effector enzymes by PI 3-kinases?

A

Inactive PDK1 is recruited to the plasma membrane and is phosphorylated by PI 3-kinases -> active PDK1 phosphorylates PKB (Akt) -> active PKB is released and will phosphorylate its substrates:
- GSK3 (glycogen synthase kinase-3): which will inactive glycogen synthase enzyme (response to insulin when glucose is high)
- BAD protein (survival pathway): will keep the BAD protein in the phosphorylated state, thereby releasing a protein called ‘’active apoptosis-inhibitory protein’’ which will prevent apoptosis from occurring

29
Q

V. Signaling with PI 3-kinase
8. How is PI 3-kinase encoded?

A
  • PI 3-kinase is encoded by proto-oncogene, a gene that could become an oncogene due to mutation or increased expression.
  • Oncogene = a gene that has potential to cause cancer.
30
Q

V. Signaling with PI 3-kinase
8. How is PI 3-kinase encoded?

A
  • PI 3-kinase is encoded by proto-oncogene, a gene that could become an oncogene due to mutation or increased expression.
  • Oncogene = a gene that has potential to cause cancer.
31
Q

V. Signaling with PI 3-kinase
9. What are the features of PTEN?

A
  • PTEN acts as a phosphatase and is encoded by tumor suppressor gene (PTEN gene).
  • Mutations of this gene are a step in the development of many cancers.
  • PTEN will dephosphorylate PI (3,4,5)-P3 to PI (3,4)-P2, reversing the action of PI 3-kinases.