Cell Signalling Flashcards

1
Q

Cell Signalling Pathway

A
  1. extracellular signal molecule
  2. receptor protein activation (conformational change in receptor)
  3. intracellular signalling proteins for signal transduction downstream
  4. effector proteins
  5. altered gene expression/metabolism/cell shape
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2
Q

Types of Intercellular signalling

A
  1. contact dependent (contact via membrane bound signal/receptor)
  2. synaptic
  • growth factors, hormones, cytokines
    2. paracrine (small distance local mediators)
    4. endocrine
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3
Q

Cytokines

A

secreted by immune cells and modulate immune response

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4
Q

Chemokines

A

subset of cytokines functioning as chemoattractants

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5
Q

Hormones

A

produced by endocrine glands and distributed by bloodstream

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6
Q

Growth factors

A

stimulate cell growth/differentiation

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7
Q

Hydrophobic signal molecules

A
  • cross plasma membrane directly
  • mainly steroids or sex hormones
  • once activated by hormone binding, nuclear receptors translocate to the nucleus and bind to DNA to regulate gene expression
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8
Q

Signal Integration

A
  • process of responding correctly to a number of different signals
  • ie. multiple different signals integrate to provoke a process
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9
Q

Signalling Context

A
  • same signal molecule elicits different response
  • context dependent
  • acetylcholine can bind to heart pacemaker cells to decrease firing, salivary gland cells to secrete enzymes, and skeletal muscle cells to stimulate contraction
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10
Q

Receptor State Changes

A
  • conformational changes in proteins link signal inputs to outputs
  • can cause PTMs, complex formation/dissociation, changes in localisation within cells
  • inputs can change the protein at each signalling ‘node’ from off to on
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11
Q

Effects of PTMs

A
  • promote/prevent protein binding
  • change conformation or activity
  • change subcellular localization
  • change proteolytic stability
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12
Q

Post Translational Modifications

A
  • writer: addition of modification
  • reader: protein binding to PTM to carry on signal
  • eraser: eraser of modification
  • eg. phosphorylation of tyr, ser, threonine
  • readers bind to phos. residue to mediate signalling and lead to output
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13
Q

Example of PTM

A
  1. tyrosine kinase/phosphatase with SH2 domain
    - receptor signalling
  2. histone acetyl transferase/deacetylase with bromo domain
    - increased transcription
  3. ubiquitin ligase/deubiquitinase with UIM domain
    - DNA damage response
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14
Q

Protein kinase

A
  • human kinome is 500 kinases (400 ser/threonine)
  • conserved structure:
  • N lobe and C lobe
  • ATP substrate binding pocket in cleft
  • gamma P of ATP transferred to protein
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15
Q

Regulation of Kinases

A
  • regulation by conformational changes and phosphorylation of activation loop
    Inactive:
  • C helix in up conformation
  • Lys-Gly salt bridge not formed
  • activation loop blocks ATP binding site for autoinhibition
    Active:
  • C helix in down conformation
  • salt bridge formed
  • activation loop moves out of ATP binding site and is phos.
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16
Q

Kinase Inhibitors

A
  • many cancer drugs target kinases
  • eg. Imatinib is an ATP competitive inhibitor targeting the Bcr-Abl fusion protein encoded by the Philadelphia chromosome (Abl is tyrosine kinase)
  • treats chronic myelogenous leukemia
17
Q

Monomeric GTPases

A
  • molecular switches
  • inactive state binds GDP
  • GEF promotes GTP exchange
  • activate state binds GTP
  • GAP promotes hydrolysis of GTP
18
Q

Signal Specificity

A
  • signalling complexes increase signalling specificity

- assembled on scaffold protein/activated receptor/iner leaflet of lipid bilayer

19
Q

Multivalency

A
  • increases specificity and affinity of molecular recognition
  • linked domains causes high affinity and specificity for tandem phosphorylated motifs
20
Q

Membrane association

A
  • reduces degrees of freedom for a productive encounter of two molecules
  • reduces 3D search to a 2D search
21
Q

Phase Transitions

A
  • phase transitions are important in multivalent signalling protein assembly
  • leads to liquid droplet formation similar to phase separation
22
Q

Persistence of signal response

A

transient

  • fast turnover of signal mediators
  • negative feedback loops
  • adaptation

stable

  • switch like behaviour
  • positive feedback loops
  • permanent decisions
23
Q

Positive feedback

A
  • switch like response
24
Q

Negative feedback

A
  • reduces signal strength/duration
  • inactivates receptor or signal protein
  • produces inhibitory protein
  • sequesters receptor
  • down regulates receptor (lysosome destruction)
25
Q

Oscillation

A
  • negative feedback with delay causes signal oscillations
  • most biological loops have built in delay as it takes time to add PTMs or convey the downstream signal
  • damped oscillations: minimal oscillation
  • robust oscillations: neg. feedback + delay + pos. feedback
  • additional pos. feedback makes system bistable
  • oscillators depend on instability of a component in the negative feedback loop
  • when all components are stable, the output peaks once and then decays into a steady inhibited state (transient)
26
Q

Xenopus oocyte cell cycle

A
  • robust natural oscillator
    Core negative feedback loop:
    The CDK-cyclin complex phosphorylates the anaphase-promoting complex (APC), which promotes Cdc20 binding. The APC-Cdc20 complex polyubiquitylates the cyclin, targeting it for destruction.

Positive feedback loop 1:
The CDK-cyclin complex phosphorylates the kinase Wee1, thereby inactivating it; Wee1 phosphorylates the CDK-cyclin complex, thereby inhibiting it (double negative loop).

Positive feedback loop 2:
The CDK-cyclin complex phosphorylates the phosphatase Cdc25, thereby activating it; Cdc25 dephosphorylates the CDK-cyclin complex, thereby activating it (double positive loop).

27
Q

Logic Gates

A
  • AND: both signals needed for output
  • NOR: neither signal needed for output
  • OR: either both or just one needed for output
  • XOR: either one or the other (not both) needed for output
28
Q

Sustained Input Detector

A
  • combining feedforward loop with an AND gate
  • achieve a transient input doesn’t lead to output
  • you want a sustained input to lead to output
  • fast branch into gate (eg. phos)
  • slow branch (eg. gene expression changes)
  • both need to occur
  • if just a blip of signal the lack of slow branch will cause no response
  • if coincident signals are detected with sustained response, both branches are on to produce a output
29
Q

Mitogen Signalling

A

example of sustained input detection

  • mitogen is a growth signal for division
  • need long presence of mitogen
  • activates MAP kinase that phosphorylates TF (slow path)
  • TF transcribe FOS1 protein
  • FOS1 is unstable and needs phos. to result in division
  • fast pathway is this stabilisation
  • MAP kinase must stay activated long enough to phos. FOS1