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).
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.
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.
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.
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 coSmad4, 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.