Chap. 16 Problem 1 Cytokine receptors and RTKs both form functional dimers on binding of ligand. Ligand binding activates cytosolic kinase domains which.

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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 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.