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Cells to Organisms - Lectures > Lecture 15. Conservation of signaling pathways between organisms > Flashcards

Lecture 15. Conservation of signaling pathways between organisms Flashcards

1
Q

What is juxtacrine signaling ?

A

Signalling by plasma membrane attached proteins. Signalling cell is adjacent to target cell

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2
Q

What is an example of juxtacrine signaling ?

A

Notch signalling pathway

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3
Q

What is the function of the Notch signaling pathway ?

A

Regulates cellular identity, proliferation, differentiation and apoptosis in animals by developmental processes such as lateral inhibition

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4
Q

What happens in the process of lateral inhibition ?

A

Adjacent and developmentally equivalent cells assume completely different fates

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5
Q

What must happen for the activation of the notch signaling pathway to occur ?

A

The ligand (Delta type) and the receptor (notch) must be be located in membranes of adjacent cells

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6
Q

What does the notch signaling pathway involve ?

A

Ligand induced protein cleavage

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7
Q

What are the key players in the basic operation of the notch pathway ?

A
  1. Delta type ligand
  2. Receptor notch
  3. Proteases
  4. CSL transcription factor
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8
Q

What is the receptor family in the notch pathway ?

A

Notch/lin-12/glp-1

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9
Q

What is the ligand in the notch pathway ?

A

Delta, serrate, delta like, jagged

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10
Q

What are the processing proteases in the notch pathway ?

A

Furins, ADAMs and secretases

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11
Q

What are the downstream effectors in the notch pathway ?

A

CBF2, Su(hairless), Lag 1

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12
Q

What is the notch protein synthesised as ?

A

A monomeric membrane protein in the endoplasmic reticulum

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13
Q

What happens to the notch protein once it is synthesised ?

A

Transferred to the golgi

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14
Q

What happens once the notch protein is in the golgi ?

A

Undergoes proteolytic cleavage by a furin protease (S1 cleavage) to generate an extracellular subunit and a transmembrane cytosolic cleavage

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15
Q

What do the two subunits of the notch receptor do ?

A

Remain non-covalently associated with each other in the absence of interaction with delta like ligand residing on an adjacent cell

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16
Q

Once the notch receptor undergoes proteolytic processing in the the golgi what happens ?

A

Transported to cell surface membrane

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17
Q

What binds with the notch ligands expressed by adjacent sending cell ?

A

The extracellular domain of the notch receptor in the signaling receiving cell

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18
Q

What induces the second proteolytic step ?

A

Binding of the receiving cell to the sending cell

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19
Q

What is the second proteolytic step ?

A

S2 cleavage by ADAM metalloproteases

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20
Q

What does S2 cleavage by ADAM metalloproteases lead to ?

A

The endocytosis of the notch extracellular domain into the ligand expressing cell

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21
Q

What happens after S2 cleavage step ?

A

S3-S4 cleavage by gamma-secretases protease to release the notch intracellular domain as a soluble protein into the cytosol

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22
Q

Where does the resulting active Notch ICD soluble protein translocate to ?

A

The nucleus and interacts with the CSL protein

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23
Q

What happens in the absence of notch-ICD ?

A

The CSL is bound to co-repressor which actively represses the transcription of notch target genes

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24
Q

What does binding of notch-ICD with CSL displace ?

A

The co-repressor

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25
Q

What does displacing the co-repressor result in ?

A

The formation of an active complex with MAML and other co-activators and leads to the transcription of notch target genes

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26
Q

What are some examples of notch target genes ?

A

HES, cyclin D1 and c-MYC

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27
Q

What happens once target genes have been expressed ?

A

Notch-ICD is downregulated

28
Q

What targets Notch-ICD to a proteasome ?

A

An E3 ubiquitin ligase attaches multiple ubiquitin molecules to notch-ICD

29
Q

What is a proteasome ?

A

A large multifunctional protease complex in the cytosol that degrades intracellular proteins marked for destruction by ubiquitin

30
Q

Where is de-regulated notch signalling found ?

A

in T-cell leukaemia, breast cancer, prostrate cancer, colorectal cancer and lung cancer as well as CNS malignancies

31
Q

What are two major classes of notch-inhibitors which may be an emerging target for cancer treatment ?

A
  1. Y-secretase inhibitors

2. Monoclonal antibodies

32
Q

What do pathways such as nutrient and energy sensing pathways in multicellular eukaryotes converge on ?

A

TOR

33
Q

What is TOR ?

A

A large protein kinase

34
Q

What does Tor kinase do ?

A

Regulates several cellular processes in response to nutritional status and signals from cell surface receptors

35
Q

What can translation initiation factors and ribosomal proteins be regulated by ?

A

Modification such as phosphorylation

36
Q

What are the two distinct mTOR containing complexes in mammalian cells ?

A
  1. mTORC1

2. mTORC2

37
Q

In addition to mTOR kinase what are the core components for mTORC1 ?

A
  1. Raptor

2. mLST8

38
Q

What controls protein synthesis in nutrient and energy saving pathways ?

A

Active mTORC1

39
Q

How does active mTORC1 control protein synthesis ?

A

By phosphorylating kinase S6K1/2 and 4E-BP1

40
Q

What do kinase S6K1/2 and 4E-BP1 do ?

A

Regulate translation

41
Q

What do kinase S6K1/2 and 4E-BP1 lead to ?

A

An increase in protein synthesis

42
Q

What is the function of S6K1/2 ?

A

Phosphorylates ribosomal proteins leading to an increase in the rate of protein synthesis

43
Q

What is the function of 4E-BP1 ?

A

Inhibits interaction of a key translation initiation factor with mRNA so inhibits protein synthesis.

When phosphorylated by mTORC1, 4E-BP1 releases the initiation factor thus stimulation translation initiation

44
Q

What is mTOR activity regulated by ?

A

G-protein RHEB

45
Q

What is Rheb activity controlled ?

A

TSC1/TCS2

46
Q

What does TSC1/TSC2 do ?

A

A Rheb GTPase activating protein which causes hydrolysis of bound GTP to GDP, thereby inactivatinf mTOR

47
Q

What happens to TCS2 in response to insulin ?

A

AKT inhibits TSC2 through phosphorylation, allowing Rheb-GTP to accumulate and activate mTORC1

48
Q

How does AMPK effect mTORC1 ?

A

Inhibits it through activation of TSC2 and inhibition of Raptor through phosphorylation of key serine residue

49
Q

What are intracellular amino acids sensed by ?

A

mTORC1 through an undefined pathway affecting Rag GTPase

50
Q

What is at the heart of life ?

A

Coupling the availability of nutrients and energy with growth factors to drive cell proliferation

51
Q

What are crucial components regulating the perception and the responses to nutrients and energy levels ?

A

mTOR and AMPK/SnF1

52
Q

What sort of relationship exists between the mTOR and AMPK pathway ?

A

An antagonistic

53
Q

What are AMPKs activated by ?

A

A decrease in energy levels sensed by an increase in the AMP/ATP ratio for AMPK or by nutrient starvation

54
Q

What is TOR kinase globally activated by ?

A

Favourable and nutrient replete conditions

55
Q

What can be found in plants ?

A

TORC1 complex

56
Q

What did TOR silencing lead to ?

A

Yellowing of leaves linked to chlorophyll breakdown and premature senescence

57
Q

What is SnRK1 ?

A

A AMPK ortholog found in plants

58
Q

What is SnRK1 implicated in ?

A

The regulation of development, growth and defence

59
Q

What is SnRK1 a central integrator of ?

A

Stress and energy modulating the expression of more than 1000 genes through the phosphorylation of various transcription factors

60
Q

What can SnRK1 phosphorylate ?

A

An inhibitory conserved serine residue in the raptor protein allowing direct control of TORC1 activity

61
Q

What represents an important regulatory pathway connecting nutrient sensing to the cell growth machinery ?

A

The functional conservation of AMPK/SNF1/SnRK1 and TOR in eukaryotes together with inhibitory phosphorylation in raptor

62
Q

What interconnects and control plant growth ?

A

Sugar signaling pathways

63
Q

What is an important factor in regulating plant growth ?

A

The cellular metabolic status

64
Q

What activates SnRK1 and what does it result in ?

A
  1. Nutrient stress

2. Inhibition of growth

65
Q

What is plant SnRK1 regulated by ?

A

Sugar phosphates

66
Q

What is SnRK1 activity repressed by ?

A

Glucose 6-phosphate and trelahose-6-phosphate

67
Q

What happens under a high metabolic status ?

A

Trelahose-6-phosphate and glucose-6-phosphate inhibit SnRK1 and the active TOR kinase then stimulates translation and growth

Cells to Organisms - Lectures (36 decks)

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