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Cell Biology > RTK Signalling > Flashcards

RTK Signalling Flashcards

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AP® Biology flashcards Biology 101 flashcards
1
Q

What are the two ways that signal transduction can be modular?

A
  1. The same protein fold/domain can be used for different downstream effects, binding to different signalling proteins
  2. The same principle, e.g. an increase in Ca2+ can be used for different outcomes, e.g. PKC and CAM kinase activation
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2
Q

Modularity is present in most signalling pathways. True or False?

A

True

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3
Q

What benefit is modularity to cell signalling pathways?

A

Modularity allows for flexible evolution and essential cross-talk between pathways

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4
Q

What are the four subfamilies of Enzyme-Linked Receptors?

A
  1. Tyrosine Kinase
  2. Guanylate Cyclase
  3. Tyrosine Phosphatase
  4. Serine/Threonine Kinase
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5
Q

Describe the transduction of a signal from a ligand to the cytosol through an Enzyme-Linked Receptor

A

Ligands induce receptor dimerisation which activates the enzymatic activity of the receptor on the cytosolic side.

This can be through mutual trans-phosphorylation of the two subunits, or recruitment of a catalytic subunit from the cytosol which is then activated.

The active enzyme will in most cases phosphorylate and thereby activate or inhibit targets to initiate signalling cascades

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6
Q

Give some examples of ligands and their specific enzyme-linked receptors

A

TGF-B and BMP -> TGFB receptors
Cytokines, Erythropoietin, Prolactin -> Cytokine receptors
EDG, PDGF, FGF, insulin, IGF-1 -> RTKs

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7
Q

Describe the conformational changes that occur when a ligand binds to an RTK

A

Ligand binding to extracellular domains brings the intracellular domains together; homodimerisation, this allows the kinase activity of one of the cytosolic domain to phosphorylate a tyrosine on the other cytosolic domain; transautophosphorylation, with causes phosphorylation of the other cytosolic domain at a tyrosine residue. *ATP

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8
Q

What structure connects the intracellular and extracellular domains of an RTK?

A

A transmembrane alpha-helix

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9
Q

What is IRS-1?

A

Insulin Receptor Substrate 1; a multi-docking scaffolding protein recruited upon activation of an RTK.

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10
Q

How is IRS-1 activated?

A

Through phosphorylation by an activated RTK after its recruitment to the cytosolic domain of the receptor

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11
Q

Explain how IRS-1 is a multi-docking/scaffolding protein

A

Phosphorylated IRS-1 recruits multiple factors that would individually be inactive but form an active complex in each others presence.

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12
Q

How does IRS-1 bind to an RTK?

A

The PTB domain, which binds to phosphotyrosine of the cytosolic domain of the receptor, is a platform for IRS-1 to bind to RTK

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13
Q

Which protein domains can bind phosphotyrosine on the cytosolic RTK?

A

PTB and SH2 domains

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14
Q

Which domains are able to bind phosphoinositides in membranes?

A

PH and PX domains

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15
Q

How does phosphorylation of tyrosine on RTKs regulate activity of SH2 and PTB domains?

A

Phosphorylation of tyrosine on cytosolic RTK enables SH2 and PTB binding while dephosphorylation prevents it.

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16
Q

How is the assembly of signalling platforms self-propagating?

A

RTK can phosphorylate itself many times

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17
Q

The first principle of domain classification is by sequence and 3D structure homology rather than function. True or False?

A

True.

Function, i.e. binding specificity, is therefore largely correct but can deviate from the classic functional classification for some domains.

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18
Q

What is the function of the SH2 domain?

A

SH2; Sarcoma/Src. Homology 2 Domain binds phosphotyrosine

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19
Q

What is the function of the SH3 domain?

A

To bind peptide sequences enriched in proline residues

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20
Q

What is the function of the PTB domain?

A

Phosphotyrosine Binding Domain

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21
Q

What is the function of the PH domain?

A

PH; Pleckstrin Homology Domain, binds phosphoinositides in membrane

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22
Q

What is the function of the PX domain?

A

PX; Plox Homology Domain, binds phosphoinositides in membrane

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23
Q

What is the function of the C2 domain?

A

2nd domain of PKC, to bind membranes in presence of Ca2+

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24
Q

What is the function of the PDZ domain?

A

To bind to ~5-7 AAs at the C-terminus of a target protein

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25
Q

Domains can be stringed together in a protein to form a scaffold on which signalling complexes can be found. True or False?

A

True.

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26
Q

The PTB domain of IRS-1 binds specifically to Tyr-P of which specific receptors?

A 
Insulin Receptor (IR) 
and interleukin-4 receptor (IL-4R)
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27
Q

How is binding specificity of the PTB domain determined?

A

The amino acid preceding the Tyr

28
Q

Which amino acid is best at determining binding specificity in IL-4R?

A

Alanine (best in IL-4R and good in IR)

29
Q

The glutamate at pY960 - 1 (preceding the phosphotyrosine) In IR reduces the affinity 50-fold compared to alanine at this positive. True or False?

A

True

30
Q

Which amino acids show very weak/no binding in the neurotrophin receptor TrkA and the EGF receptor?

A

Aspartate and Glutamine

31
Q

How is specificity determined for SH2 domains?

A

By the amino acids surrounding pTyr

32
Q

Which amino acids specify binding of SH2 domains in the SHC adaptor protein?

A

A Leu or a Val at the 3rd position after pTyr

33
Q

What is SHC?

A

An adaptor protein with SH2 and PTB domains

34
Q

Which amino acids specify binding of SH2 domains in Lck protein (a scr-related kinase)?

A

An Ile at the 3rd position after pTyr

35
Q

Which amino acids specify binding of SH2 domains in PLC-gamma-1?

A

A hydrophobic residue, e.g. Ile at the 2nd position after pTyr

36
Q

Which amino acids specify binding of SH2 domains in Syp (pTyr phosphatase)?

A

Specific residues up to 5AAs away.

37
Q

What is Phospholipase C?

A

A class of membrane-associated enzymes that cleaves phospholipids just before the phosphate group.

38
Q

Phospholipase C can only transduce RTK initiated signals. True or False?

A

False. PLC can transduce both RTK and GPCR signals.

39
Q

What is the function of PLC in the GPCR pathway?

A

PLC-beta binds with G-alpha, forming a complex which catalyses hydrolysis of PIP2 -> DAG + IP3

40
Q

What is the function of PLC in the RTK pathway?

A

RTK forms complex with PLC-gamma at intracellular domains, which catalyses hydrolysis of PIP2 -> DAG + IP3

41
Q

Which protein kinase is a common downstream target of DAG and IP3?

A

PKC

42
Q

Explain how IP3 increases cytosolic Ca2+ concentration.

A

IP3 binds to IP3-gated Ca2+ channel in ER causing local and transient Ca2+ release into cytosol.

43
Q

How is IP3 degraded/inactivated?

A

Phosphatases either remove the 4’ or 5’ phosphate or a kinase adds a 3’ phosphate.

44
Q

How are Ca2+ levels regulated in the cytosol?

A

Ca2+ channels in the plasma membrane, CRAC and P2X, and in the ER, IP3R, when activated provide a local increase in cytosolic Ca2+.

The SERCA (sarcoplasmic-endoplasmic reticulum calcium) pump constantly removes excess cytosolic Ca2+ into the ER.

45
Q

What is the cytosolic resting [Ca2+] relative to the concentrations found in ER?

A

Cytosolic is ~10,000 fold lower than in ER at resting.

46
Q

Only a 5-fold increase in cytosolic Ca2+ is needed for Ca2+ to be active as a second messenger. True or False?

A

False. Its about 10-fold but still small relative to difference in concentrations between ER and resting cytosol

47
Q

What is the calcium binding motif of PKC?

A

C2 domain

48
Q

What is the calcium binding motif of Calmodulin?

A

EF hands

49
Q

What is the result of Ca2+ binding to its motifs on calcium-binding proteins?

A

As is a highly charged species, induces a large conformational change, changing the way AAs interact with each other in the protein

50
Q

What is the function of Ca2+-bound Calmodulin?

A

Active Calmodulin binds to the helix of a kinase, resulting in autophosphorylation (of the kinase) by ATP.
E.g. CAM kinase.
This activates the kinase.

Removal of Ca2+ deactivates the calmodulin and therefore the kinase.

51
Q

What is PKC?

A

Protein Kinase C: A group of serine/threonine kinases containing a regulatory domain attached to the catalytic domain.

52
Q

What are the three historical classifications of PKC?

A
  1. Conventional (alpha, beta, gamma) - activated by DAG and Ca2+
  2. Novel (delta, epsilon, eta, theta) - activated by DAG only.
  3. Atypical (zeta) - activated by ceramide
53
Q

Describe the structure of conventional PKCs.

A

At the N-terminus, A C1 Zinc finger binding domain in regulatory subunit binding DAG/phorbol esters.

A C2 Ca2+ binding domain in regulatory subunit.

A C3 ATP binding domain in catalytic subunit.

A C4 substrate binding domain in catalytic subunit, at C-terminus.

54
Q

Describe the structure of novel PKCs.

A

C2-LIKE domain in regulatory subunit binding DAG only (not calcium) at the N-terminus.

Zinc finger also binding DAG in regulatory subunit.

C3 ATP binding domain with C4 substrate binding domain at C-terminal in catalytic subunit

55
Q

Describe the structure of atypical PKCs.

A

C2-LIKE domain binding ceramide, in regulatory subunit.

C3 ATP binding domain and C4 substrate binding domain at the C-terminus, in catalytic subunit.

56
Q

What structural features are common between the three classifications of PKCs?

A

All have a regulatory and catalytic subunit, with regulatory subunits at N-terminus and catalytic at C-terminus.

All have C3 ATP binding domain upstream from the C4 substrate binding domain, which is at the C-terminus.

57
Q

What is the kinome?

A

The human protein kinase tree constructed based on sequence homology.

E.g. RTKs, MAPKs, PKA/B/C…. etc.
~500 different human kinases in human genome!!

58
Q

Similarities between RTKs?

A

All transmembrane proteins
All receptors
All phosphorylate tyrosine
Part of enzyme-linked receptor family

59
Q

Similarities of MAPKs?

A

Similar targets and function

Similar in sequence

60
Q

Similarities of PKA/B/Cs?

A

Catalytic domains and target domains can be similar but can have different regulatory domains (e.g. the classifications of PKCs)

61
Q

What are the cellular effects of PKC-alpha?

A

Role in autoimmunity and transplant rejection
Promotes IL2 production
Promotes IgG switching

62
Q

What are the cellular effects of PKC-beta?

A

Cell migration

IL2 production

63
Q

What are the cellular effects of PKC-delta

A

Promote apoptosis
Inhibit IL2 production
Role in autoimmunity and transplant rejection

64
Q

What are the cellular effects of PKC-zeta?

A 
Cell migration
IL2 production
Inhibits cell adhesion
Inhibits apoptosis 
Inhibits effector cell differentiation
65
Q

What are the cellular effects of PKC-epsilon?

A

Inhibits apoptosis

IL2 production

66
Q

What are the cellular effects of PKC-theta?

A

Promotes cell adhesion, IL2 production, effector cell differentiation, and roles in autoimmunity and transplant rejection.

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