Intro to Cell Signaling Flashcards
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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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What are some various inputs involved in cell signaling?
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- environmental stresses
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What are some of the various outputs involved in cell signaling?
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Feedback
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Sometimes outputs interact in feedback mechanism to affect inputs
how so?
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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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autocrine
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paracrine signaling
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endocrine signaling
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Give examples of each:
1 - autocrine signaling
2 - paracrine signaling
3 - endocrine signaling
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Changes may be extracellular or intracellular.
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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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What are some characteristics of cell signaling?
- 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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What are some characteristics of gene expression?
- slow ON and OFF (minutes to hours)
- stable changes (hours to years)
- limited spatial responses
- energetically costly (transcription and translation)
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What are some advantages of cell signaling?
quick, energetically cheap
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What is the general scheme of signal transduction?
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When/how is signal transduction initiated?
signal transduction is initiated upon recognition of the input (stimulus) by its receptor
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By what are receptors classified?
- according to their cellular localization
| - shared mechanism of action
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What are four classifications of receptors (these aren't the only ones)?
- cell surface receptors
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What are the four types of cell surface receptors (there are more than these)?
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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What are the different types of intracellular receptors?
1 - Nuclear Receptors (NR)
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Nuclear Receptors (NR)
- a superfamily of receptor (~48 members in the human genome)
- NRs have
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Toll-like Receptors (TLRs) and NOD-like receptors
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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Intracellular ligand-gated ion channels
- found inside cells (as well as...something previously)
- PIP2 is embedded in plasma membrane; cleaved by phospholipase C..blah blah
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Recognition of the external stimulus by the receptor provides the first message in signal transduction
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firt message followed by
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Relay and Amplification
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What regulates the activation of signaling pathways?
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?
- 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
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
- 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
- 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?
- 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?
- 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?
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
- 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
targets kinases
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plx
competitive ATP inhibitor
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plx
| B-raf
- 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
Sos activates
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The Mitogen-activated protein (MAP) kinase cascade
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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