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Blueprint Series

Complete Solution
Chapter 16

16
SIGNALING PATHWAYS THAT
CONTROL GENE EXPRESSION

REVIEW THE CONCEPTS
1
...
Upon dimerization, one of the poorly active cytosolic
kinases phosphorylates the other on a particular tyrosine residue in the activation lip
...
Both cytokine receptors
and RTKs then serve as docking sites for signaling molecules that bind to these phosphotyrosine sites
...

2
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When GRB2 binds the Epo receptor, the Ras/MAP kinase signaling pathway is
activated, resulting in the translocation of MAP kinase to the nucleus, where it
phosphorylates and regulates the activity of transcription factors
...
When JAK phosphorylates and activates STAT5, STAT5 itself translocates to the
nucleus as a homodimer and functions as a transcription factor
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In most normal people and even elite athletes, RBCs comprise 40–50% in men and 35–45% in
women of the volume of the blood (hematocrit)
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65

3
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4
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GRB2 binds to phosphotyrosine residues on activated receptor tyrosine kinases
via its SH2 domain and binds to the guanine nucleotide exchange factor Sos via
two SH3 domains
...
Although
all SH2 domains bind to phosphotyrosine residues, specificity is determined by
the conformation of the binding pocket, which interacts with amino acids on
the carboxy-terminal side of the phosphotyrosine
...
Negative feedback occurs when a signaling pathway induces expression or activation of its own inhibitor
...
Binding induces a conformation change that activates SHP1, which is
in close proximity to JAK (associated with EpoR)
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The erythropoietin signaling
pathway also possesses negative feedback that triggers long-term downregulation in which STAT proteins induce the expression of SOCS proteins
...
One SOCS protein also binds the activation lip of JAK2 and inhibits
its kinase activity
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(b) TGFb signaling induces the expression of SnoN and Ski, two proteins that bind to Smads and
inhibit their ability to regulate transcription
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6
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For example, RasD is constitutively active because it cannot bind GAP and
therefore remains in the GTP-bound, active state even when cells are not stimulated by growth factor to activate a receptor tyrosine kinase
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a
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b
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c
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7
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When the mating factor signaling pathway is activated,
Ste7, Ste11, and the other relevant kinases in the cascade form a complex with the
scaffold protein Ste5
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8
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In muscle cells, insulin-stimulated activation of protein kinase B causes fusion of intracellular vesicles containing the GLUT4 glucose transporter with the plasma
membrane, resulting in increased influx of glucose
...

9
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Loss-of-function mutations are cancer
promoting because constitutive activation of protein kinase B results in constitutive phosphorylation and inactivation of proapoptotic proteins such as Bad
and Forkhead-1
...
A gain-of-function mutation in PTEN phosphatase would promote
cell death by causing the apoptotic pathway to be active even in the presence of
survival factors that signal through protein kinase B
...
In multiple cell types, TGFb activates a conserved signaling pathway that results
in translocation of Smad2 or Smad3 to the nucleus in complexes with co-Smad4
...
The complement of these other transcription
factors is cell-type specific, and thus the TGFb signaling pathway will induce the
transcription of different genes in different cell types
...
TGFb binds to its type II receptor either directly or when presented by the type
III receptor
...
When the type II receptor binds TGFb, it forms a tetrameric complex consisting of two molecules of the type II receptor and two molecules of the type I
receptor
...
The type I receptor then phosphorylates R-Smad2 or R-Smad3, inducing a conformational change that exposes
a nuclear localization signal on the R-Smad
...
This complex translocates to the nucleus, where it interacts with
other transcription factors to elicit changes in gene expression
...


Maintenance of Smad activity in the nucleus thus requires continued activation
of Smads by TGFb-activated receptors
...
Hedgehog is covalently linked to cholesterol and also has a palmitoyl group
added to the N-terminus
...
Together, these modifications make
the Hh signaling domain hydrophobic so that it remains tethered to the cell
membrane
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13
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Nonfunctional versions of either Hedgehog or Smoothened protein would
block the Hh signaling pathway, yielding the same phenotype
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14
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Kif3A moves Smo along the
microtubules in the core of the cilium up the ciliary membrane
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The dynein motor protein moves the activated
Gli to the base of the cilium from where Gli moves into the nucleus to activate
gene transcription
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15
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Thus,
the signal cannot be switched off rapidly as with a kinase-induced signal that
can be reversed by the action of an opposing phosphatase
...
However, synthesis of the I-kB inhibitor de novo is a relatively slow process, and thus, the NF-kB pathway can remain active for some
time after the original stimulus, such as TNF-a, is removed
...
Stimulation of a cell by an infectious agent or inflammatory cytokine activates
b kinase to phosphorylate I-kBa
...
The E3 ligase TRAF6 polyubiquitinates I-kBa lysine 63
(K63)
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17
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Unlike EGF precursors, which can be cleaved by proteases to release diffusible EGF signaling molecules, Delta remains intact for

signaling and therefore can only activate Notch receptors on
neighboring cellswith which it is in direct contact
...
g-secretase is an intramembrane protease
...
Unfortunately, g-secretase also generates
the cytosolic fragment of Notchthat translocates to the nucleus as part of
that signaling pathway
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