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Foundations Week 7 > Intro to Cell Signaling > Flashcards

Intro to Cell Signaling Flashcards

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PLX

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How do cells process information?

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the role of the cell signaling systems is to receive input from the environment and, on the basis of that input, generate an appropriate output response -
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Cells able to sense

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8
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What are some various inputs involved in cell signaling?

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  • environmental stresses

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9
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What are some of the various outputs involved in cell signaling?

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12
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Feedback

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Sometimes outputs interact in feedback mechanism to affect inputs

how so?
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13
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What are three examples of extracellular signaling?

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  • autocrine signaling
  • paracrine signaling
  • endocrine signaling
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14
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autocrine

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paracrine signaling

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endocrine signaling

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17
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Give examples of each:
1 - autocrine signaling
2 - paracrine signaling
3 - endocrine signaling

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21
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Changes may be extracellular or intracellular.

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22
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What is signal transduction?

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includes the mechanism by which inputs are sensed and how recognition of input produce specific rapid cellular responses
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25
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What are some characteristics of cell signaling?

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  • enables transmission from outside of cell to nucleus
  • fast ON and OFF (seconds to minutes)
  • transient changes (minutes to hours)
  • spatial/directional responses and organization
  • energetically cheap (no protein synthesis; maybe just a few ATP used)
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26
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What are some characteristics of gene expression?

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  • slow ON and OFF (minutes to hours)
  • stable changes (hours to years)
  • limited spatial responses
  • energetically costly (transcription and translation)
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27
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What are some advantages of cell signaling?

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quick, energetically cheap

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28
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What is the general scheme of signal transduction?

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31
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When/how is signal transduction initiated?

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signal transduction is initiated upon recognition of the input (stimulus) by its receptor

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32
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By what are receptors classified?

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  • according to their cellular localization

- shared mechanism of action

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33
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What are four classifications of receptors (these aren’t the only ones)?

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  • cell surface receptors

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34
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What are the four types of cell surface receptors (there are more than these)?

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1 - Ligated-ion channels
2 - G-protein coupled receptors (GPCRs) (vision, taste smell, neurotransmitter release, etc)
3 - Receptor protein kinases
4 - Protein kinase-associated receptors

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35
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What are the different types of intracellular receptors?

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1 - Nuclear Receptors (NR)

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36
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Nuclear Receptors (NR)

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  • a superfamily of receptor (~48 members in the human genome)
  • NRs have

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37
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Toll-like Receptors (TLRs) and NOD-like receptors

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can be found in cytoplasm or embedded in …

  • bind ligand in intracellular compartments (endosomes) or the cytoplasm
  • these receptors bind viral nucleic acids and bacterial cell wall components and induce transcription of pro-inflammatory

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38
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Intracellular ligand-gated ion channels

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  • found inside cells (as well as…something previously)
  • PIP2 is embedded in plasma membrane; cleaved by phospholipase C..blah blah
    etc
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39
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Recognition of the external stimulus by the receptor provides the first message in signal transduction

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40
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firt message followed by

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41
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Relay and Amplification

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42
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What regulates the activation of signaling pathways?

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activation of signaling pathways is tightly regulated by a variety of molecular mechanisms that efficiently terminate the signaling response

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What are two classic ways in which signals can be terminated?

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  • receptor internalization/down-regulatin (operates on a time scale a few minutes) (receptor is endocytosed, part degraded
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  • receptor desensitization (operates within milliseconds
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Receptor Internalization

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upon ligand binding, activated receptors auto-phosphorylate and recruit ubiquitin-ligases (CbI). CbI ubiquitinates the receptor, leading to engagement of the endocytic machinery.
- autophosphorylated EGFR recruits proteins through its phopho- etc

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Receptor Desensitization

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  • operates within milliseconds to rapidly deactivate receptors
  • conformational changes induced by ligand to GPCRs recruit GPCR kinases (GRKs) which phosphorylate the GPCR C-terminal tail
  • this recruits arrestin which blocks G protein activation
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RD

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  • activated GPCR stimulates GRK to phosphorylate the GPCR on multiple sites
  • ATP –> ADP
  • arrestin binds to phosphorylated GPCR
  • now desensitized

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What do phosphatases do?

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  • remove phosphate / oppose activity of kinases
  • catalyze the removal of covalent phosphate modifications on protein side chains to oppose the phosphorylation reaction catalyzed by kinases
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What are the two classes of phosphatases?

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  • pSer/Thr phosphatases (there are 26)

- pTyr phosphatases (107)

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Example of phosphatases:

Shp1 and Shp2 are tyrosine phosphatases that do what?

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they are recruited to activated receptors via their SH2 domains and dephosphorylate and inactivate RTKs

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Ubiquitin-mediated degradation

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  • ubiquitin is a conserved protein (small protein)
  • sites of linkage include the C-terminus, K48, and K63
  • linkage of the C-terminus to K48 orK63 generates polyubiquitin chains with different structures
  • K48-linked chains are targeted for proteasomal degradation
  • whereas, K63-linked chains target the substrate to different compartments (sorted into different compartments, ex endosomes)
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Ubiquitin mediated degradation

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  • processive protein digestion by the proteasome
  • the proteasome cap recognizes a substrate protein marked by a polyubiquitin chain, and subsequently translocates it into the proteasome core where it is digested
  • ubiquitin is monomerized and recycled

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PLX4032

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plx

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targets kinases

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plx

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competitive ATP inhibitor

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plx

B-raf

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  • designed to bind specifically to a kinase called B-Raf
  • received FDA approval Aug 2011
  • the first drug designed using fragment-based lead discovery to gain approval
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Kinase function

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EGFR - a receptor tyrosine kinase

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Sos activates

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The Mitogen-activated protein (MAP) kinase cascade

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it is a system-amplified signal; involves three kinases (MAPKKK, MAPKK, MAPK)

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Raf

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EGF receptor forms scaffold when activated -etc

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Foundations Week 7 (10 decks)

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