SIGNAL TRANSMISSION WITHIN THE CELL

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SIGNAL TRANSMISSION WITHIN THE CELL

• Nela Pavlíková
• nela.pavlikova_at_lf3.cuni.cz

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G-PROTEIN COUPLED RECEPTOR
- 7 transmembrane segments
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G-protein

• heterotrimer, composed of 3 different subunits
  a, b, g
• a subunit 33-55kD
• - binding place for GDP / GTP
• - intrinsic hydrolytic activity for GTP (it
  binds GTP activation ? hydrolyzing of
  GTP to GDP deactivation)
• - in deactivated state - it has bound GDP
  molecule
• - it is associated with Gb/g complex
• b subunit 35kD
• g subunit 15kD
• - creates Gb/g complex
• mammals 20 different G proteins (each contains
  unique Ga subunit one of 5 b
  subunits and one of 12 g subunits)

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Gai
Gas
Gaq
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Gas

• stimulates adenylyl cyclase ? synthesis of cAMP ?
  activation of protein kinase A (PAK) ?
  phosphorylation of nearby substrates
• cholera toxin it keeps Gas permanently activated
  ? ?cAMP
• Gai
• after activation it inhibits adenylyl cyclase ?
  ?cAMP
• pertussis toxin Gai subunit unable to release
  GDP ? incapable of activation ? cannot inhibit
  adenylyl cyclase
• cAMP is involved in regulation of many ion
  channels

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Gaq

• not influenced by cholera toxin nor pertussis
  toxin
• phospholipase Cb ? inositol-3-phosphate (IP3) ?
  ?Ca2 in cell ? CaMKII
• ? diacylglycerol (DAG) ? protein kinase
  C
• both pathways lead to phosphorylation of nearby
  proteins

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Gat

• transducin
• sensitive to pertussis toxin ? incapability to
  release GDP ? inhibition of signalization
• Vision t1 black-and -white
• t2 colors
• occurrence retina, some stem cells
• effector phosphodiesterase-6 (PDE6)
• ? degradation of cGMP

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Gao

• other
• effectors not known
• sensitive to pertussis toxin ? incapability to
  release GDP ? inhibition of signalization
• occurrence neural and endocrine tissues, mitotic
  spindle
• early development effect of serotonin on neuron
  migration

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Ga12/13

• activation of REF (Rho guanine-nucleotide
  exchange factors) ? activation of Rho proteins
• occurrence ubiquitous

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RECEPTOR TYROSINE KINASE
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RECEPTOR TYROSINE KINASE

• growth factors, cytokines, hormones
• 17 subfamilies of receptors
• dimerization of receptors necessary (even
  tetramers)
• only one transmembrane segment (N-end
  extracellular, C-end intracellular)
• tyrosine phosphorylation creation of binding
  domains for cytosolic signaling proteins ?
  binding ? activation of signaling pathways
• cytosolic signaling proteins e.g. Src,
  phospholipase Cg, PI3-kinase
• domains for binding on phosphorylated tyrosines
• SH2 domain (src), PTB domain (PI3-kinase)

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RECEPTOR TYROSINE KINASE

• endocytosis of activated receptor
• destruction of receptor in lysosome ? binding of
  ubiquitin molecule on kinase
• endocytosed receptor signalization e.g. NGF

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RECEPTOR TYROSINE KINASE

• Ras, Rho - monomeric GTPases
• - anchored in the inner membrane
• - a part of receptor tyrosine kinase signaling
  pathway
• - activation GEF (guanine nucleotide exchange
  factor)
• - inhibition GAP (GTPase activating factor)
• ?
• resistance ? cancer
• Ras ? MAP kinase ? signalization into nucleus (?
  e.g. cell proliferation)
• Rho ? connect RTK with cytoskeleton (? cell
  shape, motility, adhesion)

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RECEPTOR TYROSINE KINASE
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RECEPTOR TYROSINE KINASE

• PI-3 kinase - Akt

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RECEPTORS ASOCIATED WITH TYROSENE KINASE

• JAK-STAT

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RECEPTOR SERINE/THREONINE KINASE

• ligand e.g. TGF-b
• SmaDs ? regulatory protein
• endocytosis ? activation
• ? degradation

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NUCLEAR RECEPTORS

• their ligands can cross the cytoplasmic membrane
  on their own
• transcription factors (in activated form they
  start transcription of target genes)
• nuclear receptors activated by ligand vs.
  orphan receptors
• type I receptor in cytosol ? ligand binding ?
  homodimerization
• ? transport into nucleus ? binding on
  response element part of DNA ? start of
  transcription
• type II receptor as heterodimer with RXR (and
  some corepressors) bound in nucleus on
  response element ? ligand into nucleus?
  binds to receptor ? dissociation of
  corepressors ? start of transcription

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answer on the question from the last
seminarsynthesis of thyroid hormones