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topics to cover
EGF vs. NGF endosomal signaling
anchoring & scaffolding proteins
signaling crosstalk
post-transcriptional regulation
transcriptional control
CRE/CREB, kinase signaling pathways
nuclear receptor signaling
chromatin structure
epigenetic regulation
EGF vs. NGF signaling
EGF vs. NGF signaling
EGF vs. NGF signaling
EGFR
EGF vs. NGF signaling
Trk
EGF vs. NGF signaling
Trk: clathrin-independent endocytosis
arrows =
clathrin-coated pit
** Trk is
black dots = TrkB endocytosed
in a manner
that is
independent
of clathrin
EGF vs. NGF signaling
Trk: Pincher-mediated endocytosis
control:
normal ** Trk endocytosis is Pincher-
endocytosis dependent
EGF vs. NGF signaling
Trk: Rac-mediated endocytosis
control:
normal ** Trk endocytosis is Rac-
endocytosis dependent
EGF vs. NGF signaling
Trk: Pincher/Rac-
mediated endocytosis
mechanism
x x
x x
EGF vs. NGF signaling
molecular basis: endocytosis
multi-vesicular body
retrograde endosomal signaling in the
axon
the chamber culture model
are they
active?
retrograde endosomal signaling in the
axon
the chamber culture model
retrograde endosomal signaling in the
axon
the chamber culture model
retrograde endosomal signaling in the
axon
molecular components of
the signaling endosome
anchoring & scaffolding proteins
nomenclature:
anchoring:
bringing signaling components to a specific
subcellular location
scaffolding:
bringing multiple signaling components
together in close proximity to each other
purpose?
efficient signaling
anchoring & scaffolding proteins
anchoring & scaffolding proteins
anchoring & scaffolding proteins
ARMS
anchoring & scaffolding proteins
Gab1
anchoring & scaffolding proteins
green = PKA
anchoring & scaffolding proteins
PI3K
PKB/Akt
endpoint convergence: TH
endpoint convergence: CREB
computational modelig
control of gene expression
RNA interference
post-transcriptional
regulation
translational
regulation
Erk
MNK1
eIF4E
post-transcriptional
regulation
translational mTOR
regulation eIF4E
4E-BP
Thestepsofeukaryoticposttranscriptionalprocessing
Decay / storage
Transcription
P-bodies / Stress Granules
1 2 3 3 4 5 General
translation
Local AAA
A
translation
AA
splicing 1 2 3 4 5 12345
Cleavage/ 1 2 3 4 5 A200
polyadenylation
mRNP
packaging
Nucleus Export
Cytoplasmic
factors mRNAtransport/localization
Localized mRNAs play a critical role in the local control of translation
Induced localization and translation of mRNAs
control axon growth
transcriptional control
transcriptional control:
cAMP responding element (CRE)
1986
necessary &
SST 5 flanking sufficient for
cAMP-mediated
response
palindromic
CAT sequence
(TGACGTCA)
within 100 bp of
TATA-box
less active if
moved further
Common Reporter Assays
increasing
CAT
acetylated
unacetylated
chromatography
transcriptional control:
CRE-binding protein (CREB)
Protein Kinase A acts in the nucleus Enhancers are binding sites for activators
transcriptional control:
CRE-binding protein (CREB)
Alpha-helix
MG 2+
transcriptional control:
CRE-binding protein (CREB)
MAPK
rsk
transcriptional control:
CREBs interaction partner
transcriptional control:
JAK/STAT signaling
transcriptional control:
serine/threonine kinase receptors
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
chromatin structure remodeling
transcriptional control:
chromatin structure remodeling
transcriptional control:
chromatin structure remodeling
transcriptional control:
chromatin structure remodeling
the histone code
transcriptional control:
chromatin structure remodeling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
on
off
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
hormone & nuclear receptor signaling
transcriptional control:
chromatin structure remodeling
transcriptional control:
epigenetic modulation
transcriptional control:
epigenetic modulation
transcriptional control:
epigenetic modulation
transcriptional control:
epigenetic modulation
GR levels
?
behavior
GR
GR levels
behavior
transcriptional control:
epigenetic modulation
behavior
GR levels
transcriptional control:
epigenetic modulation
behavior
GR levels