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CELL II > Receptors in Metabolic Signalling > Flashcards

Receptors in Metabolic Signalling Flashcards

1
Q

Features of enzyme linked receptors?

A
  • Mostly single transmembrane domain receptors
  • Activation leads to activation of a receptor kinases
  • Activation leads to activation of multiple signalling pathways
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2
Q

What’s tyrosine receptors kinase involved with?

A

Insulin
Epidermal growth factor (EGF)
Platelet derived growth factor (PDGF)

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3
Q

What’s JAK/STAT involved with?

A

Growth Hormone

Interferon

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4
Q

What’s Serine Threonine receptor kinase involved with?

A

TGFβ

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5
Q

What do enzyme linked receptors regulate?

A 
Cell growth
Division
Differentiation
Survival
Migration
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6
Q

What does inappropriate activation of enzyme linked receptors associated with?

A

disease particularly cancer

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7
Q

Describe tyrosine kinase activity

A
  • Dimerisation brings 2 receptor molecules together allowing phosphorylation of each other
  • Not all tyrosine residues can be phosphorylated
  • The phospho-tyrosine together with surrounding AA are recognised by SH2 domains of other proteins allowing them to bind + undergo activation
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8
Q

What’s Grb-2?

A

growth receptor bound protein 2

adaptor protein

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9
Q

Why is Ras an important protein?

A

regulates cellular activation + growth.

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10
Q

What are mutations in Ras are common in?

A

many tumours

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11
Q

Role of Grb-2?

A

recognises receptor via SH2 domain

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12
Q

Describe multiple pathways via activation of tyrosine kinase receptors

A
  • phosphylated tyrosine activates Ras
  • Grb-2 recognises receptor via SH2 domain
  • activates Grb-2
  • Ras GEF (guanine nucleotide exchange factor) binds to Grb-2 via SH3 domain
  • Ras activated by phosphorylation
  • cellular activation

-PI 3-kinase activated by phosphorylating inositide phosphates within plasma membrane
-allows other molecules to bind to inositide phosphates
eg PDK (phosphoinositide-dependent protein kinase)

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13
Q

Describe regulation of Ras activity

A
  • exchange of GDP -> GTP when protein activated
  • recruits protein RAF
  • process sped up by protein guanine nucleotide exchange factor (GEF)
  • GTP binding proteins have GTPase activity
  • GTPase activity slowly de-phosphorylates Ras inactivating it
  • aided by GTPase-activating proteins (GAP)
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14
Q

Role of GTPase-activating proteins (GAP)

A

aids de-phosphorylation of Ras from 30 mins to 10⁵ fold

to down-regulate this process so there isn’t overstimulation of the cell

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15
Q

Describe effect mutations of Ras

A

30% of human tumours
prevent hydrolysis of GTP -> GDP similar to cholera toxin + mutation in Gas results in pituitary tumours. Mutations in Ras-GAP also have the same effect.

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16
Q

Structure of insulin receptor?

A

2α + 2β subunits linked by disulphide bridges

has tyrosine kinase activity

17
Q

Describe effect of binding of insulin

A
  • binding of insulin results in auto-phosphorylation of 2β subunits
  • activation of receptor leads to activation family of small protein substrates - IRS
  • IRS recruited via phosphorylated tyrosines on β chain with SH2 domains on IRS –> phosphorylation
  • generation of more phosphorylated tyrosines
  • recruits more proteins:
  • IRS activates PI3K
  • activate PKB
  • PKB stimulates glycogen synthesis, protein synthesis, increased expression of GLUT transporters on membrane

-insulin also recruits Ras + PLC (involved in generation of IP3)

18
Q

Diff between insulin vs EGF receptor?

A

already dimerised so dimerisation is required but not sufficient for activation

19
Q

How are receptor kinases inactivated?

A
  • de-phosphorylation –> inactivation
  • phosphatases activated due to receptor activation
  • so signalling process sets in motion events that lead to signal termination
  • small g-proteins have intrinsic GTPase activity
  • receptor internalisation
20
Q

What does loss of phosphatase activity mean?

A

cannot inactivate receptor –> excessive stimulation of the downstream pathways

21
Q

What’s Herceptin?

A

monoclonal antibody that targets EGF receptor blocking its action

22
Q

What happens if EGF receptor is mutated?

A

can dimerise in absence of EGF so not dependent on EGF

Ras may lose its GTPase activity, so it

23
Q

What happens if Ras loses its GTPase activity?

A

can no longer turn off its activity –> inappropriate growth

24
Q

Receptor tyrosine kinase summary

A
  • Superfamily: Consist of a ligand binding domain + protein tyrosine kinase domain
  • Primarily control cell growth + differentiation
  • Consists of single transmembrane protein except insulin receptor
  • Activation –> phosphorylation specific tyrosine residues in an AA sequence
  • Phosphotyrosine interacts with proteins that contain SH2 domains
  • SH2-containing proteins include PI-PLCg and PI3K which generate 2nd messengers
25
Q

What’s the Jak-STAT signaling pathway activated by?

A

Growth hormone

26
Q

Describe binding of GH receptor

A
  • binding of GH to receptor
  • Jaks cross-phosphorylate each other on tyrosines
  • activated Jaks phosphorylate receptors on tyrosines
  • phosphorylation of adjacent chain
  • recruitment of STAT (signal transducer and activator of transcription) on phosphotyrosines
  • Jaks phosphorylate them
  • STAT dissasociate from receptor + dimerised via SH2 domain
  • transported to nucleus
  • causes regulation of various genes via transcription
27
Q

Importance of GH receptor?

A

cytokine binding

28
Q

What’s tyrosine kinase activity in GH receptor provided by?

A

recruitment JAK protein

29
Q

What’s STAT?

A

signal transducer and activator of transcription

30
Q

How GH affects GH receptor?

A
  • Absence = receptors exist as monomers
  • Binding = conformational changes permitting single GH to bind 2 receptor molecules -cooperative effect
  • Intracellular domains of the receptor also brought together
31
Q

Describe features of JAK2?

A
  • Anchored to the membrane
  • Has two kinase domains
  • Dimerization leads to phosphorylation + activation of JAK
  • Activation of JAK2 by cross phosphorylation leads to phosphorylation of other proteins
32
Q

Role of phosphotyrosine?

A

acts as docking site for proteins that contain SH2 domain

33
Q

Why’s STAT dimerised?

A

stable dimer has a strong affinity for specific DNA binding sites + regulates gene expression

34
Q

Describe binding of TGF-β to receptor

A
  • serine/threonine kinase domain phosphorylates serine/threonine
  • receptor dimerisation
  • phosphorylation
  • interacts with smad 2 +3
  • associated with smad 4
  • migrates to nucleus
  • binds to specific promotors
  • specific activation of transcription

CELL II (9 decks)

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