Chap. 16 Problem 1

1
Chap. 16 Problem 1
Cytokine receptors and RTKs both form functional
dimers on binding of ligand. Ligand binding
activates cytosolic kinase domains which
cross-phosphorylate the two monomers of the
dimeric receptor (Fig. 16.3). Phosphorylation
first occurs at a regulatory site within the
kinase domains known as the activation lip.
Phosphorylation of the lip causes conformational
changes that allow the kinase domain to
phosphorylate other tyrosine residues in the
receptor. Phosphotyrosine residues serve as
docking sites for signal transduction proteins.
The major difference between these two classes of
receptors is that RTKs have intrinsic tyrosine
kinase activity that traces to a region within
their cytosolic domains. In contrast, cytokine
receptors lack intrinsic tyrosine kinase activity
and are phosphorylated by associated kinases
called Janus kinases (JAKs).
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Chap. 16 Problem 6a b
In constitutive activation, a protein remains
active even in the presence of regulatory
processes that normally would switch the activity
of the protein off. In the case of the RasD
mutant, which is a dominant gain-of-function
mutant, Ras is constitutively active because it
cannot bind GAP (GTPase activating protein).
Constitutively active Ras promotes cancer by
activating cell proliferation even in the absence
of growth factors.
In the case of Smad3, a mutation that allows
Smad3 to bind Smad4, enter the nucleus, and
activate transcription independent of
phosphorylation by the TGFß receptor would make
Smad3 constitutively active. For MAP kinase, a
mutation that activates its kinase activity
independent of MEK would make MAP kinase
constitutively active.
3
Chap. 16 Problem 8
PI-3 kinase and protein kinase B (PKB) act
together in a signaling pathway involving
phosphatidylinositol 3-phosphate compounds. PI-3
kinase synthesizes these compounds after it is
activated by the insulin receptor. PKB is
recruited to the membrane via binding to PI
3-phosphates (Fig. 16.26). There it is
phosphorylated and activated by the PDK1 2
kinases. Activated PKB then enters the cytosol,
where it phosphorylates target proteins. In
insulin receptor signaling in muscle cells, PKB
phosphorylates and inactivates glycogen synthase
kinase, preventing the inactivation of glycogen
synthase. Glycogen synthesis can then occur.
Signaling also causes the GLUT4 glucose
transporter to move to the plasma membrane and
transport glucose into the cells for storage in
glycogen.
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Chap. 16 Problem 9
The PTEN phosphatase is important in
down-regulating signaling by the PI-3 kinase/PKB
pathway. PTEN hydrolyzes 3-phosphates in
phosphatidylinositol compounds, thereby reducing
the activity of PKB. Loss-of-function mutations
in PTEN are cancer-promoting due to the fact that
PKB phosphorylates and inactivates proteins
(e.g., Bad) that are pro-apoptotic. In contrast,
constitutively active PTEN would stimulate
apoptosis even in the presence of growth factors
that signal via PKB. Regulation of the apoptosis
pathway is covered in Chap. 21.
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Chap. 16 Problem 10
The TGFß signaling pathway is highly conserved
among different cell types. In this pathway, the
Smad2 or Smad3 transcription factors are
activated by phosphorylation, combine with
co-Smad4, and translocate to the nucleus. There
they interact with other transcription factors
and regulate the expression of target genes (Fig.
16.28). Because the types of interacting
transcription factors are cell-type specific, the
TGFß signaling pathway induces transcription of
different genes in different cell types.