Appendix C
Signaling Pathways

Seventeen intercellular signal transduction pathways are currently known with regard to the identity of their ligands, transduction intermediates, kinases, and targets. These are illustrated in Panels 1-17. Several were discovered in the course of the analysis of developmental mutants of Drosophila. Since no new mutant has been discovered recently in the continuing analysis of mutants, it is expected that most are already known. Pathways 1-6 are used extensively in early development, for example, axis specification and germ layer formation, as well as later. Pathways 7-10 are used in later development, including organogenesis and tissue renewal. Pathways 11-17 are used extensively in the physiological function of differentiated cells of the fetus, juvenile, and adult.

Approximately twelve intracellular pathways of checkpoint controls and molecular stress responses are currently known. Three are illustrated in Panels 18 and 19, and several are listed in Table 6-7. Panel 18 shows the ER-Golgi unfolded protein response, a molecular stress response of the cell to various chemical (e.g., ethanol, dithiothreitol) or physical (e.g. heat) conditions that lead to loss of function by protein unfolding (“denaturation”). The response leads to increased chaperone protein levels in the ER and Golgi, which increase refolding and restore function. The pathway also acts as a G1/S checkpoint control when naturally unstable proteins are produced. Panel 19 shows the p53 related stress response to DNA damage (genotoxic stress) leading to G1/S or G2/M arrest until repair is completed (upper half of panel). The pathway also acts as a checkpoint control monitoring DNA synthesis, imposing G2/M arrest until it is finished, via phosphorylation of the cdc25 phosphatase (lower half of panel).



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Scientific Frontiers in Developmental Toxicology and Risk Assessment Appendix C Signaling Pathways Seventeen intercellular signal transduction pathways are currently known with regard to the identity of their ligands, transduction intermediates, kinases, and targets. These are illustrated in Panels 1-17. Several were discovered in the course of the analysis of developmental mutants of Drosophila. Since no new mutant has been discovered recently in the continuing analysis of mutants, it is expected that most are already known. Pathways 1-6 are used extensively in early development, for example, axis specification and germ layer formation, as well as later. Pathways 7-10 are used in later development, including organogenesis and tissue renewal. Pathways 11-17 are used extensively in the physiological function of differentiated cells of the fetus, juvenile, and adult. Approximately twelve intracellular pathways of checkpoint controls and molecular stress responses are currently known. Three are illustrated in Panels 18 and 19, and several are listed in Table 6-7. Panel 18 shows the ER-Golgi unfolded protein response, a molecular stress response of the cell to various chemical (e.g., ethanol, dithiothreitol) or physical (e.g. heat) conditions that lead to loss of function by protein unfolding (“denaturation”). The response leads to increased chaperone protein levels in the ER and Golgi, which increase refolding and restore function. The pathway also acts as a G1/S checkpoint control when naturally unstable proteins are produced. Panel 19 shows the p53 related stress response to DNA damage (genotoxic stress) leading to G1/S or G2/M arrest until repair is completed (upper half of panel). The pathway also acts as a checkpoint control monitoring DNA synthesis, imposing G2/M arrest until it is finished, via phosphorylation of the cdc25 phosphatase (lower half of panel).

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 1A. Wnt pathway via β–catenin 1B. Wnt pathway via JNK (planar cell polarity pathway)

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 2. Receptor serine/threonine kinase (TGF-β receptor) pathway 3. Hedgehog pathway (Patched receptor protein)

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 4. Receptor tyrosine kinase pathway (small G-protein [Ras] linked)

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 5. Notch-Delta pathway 6. Receptor-linked cytoplasmic tyrosine kinase (cytokine) pathway

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 7. IL1froll receptor; NF-kappaB pathway 8. Nuclear hormone receptor pathway

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 9. Apoptosis pathway (cell death pathway)

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 10. Receptor protein tyrosine phosphatase (RPTPs) pathway 11. Receptor guanylate cyclase pathway

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 12. Nitric oxide receptor pathway 13. G-protein coupled receptor (large G-protein) pathway

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 14. Integrin pathway 15. Cadherin pathway

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 16. Gap junction pathway 17. Ligand-gated cation channel pathway

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 18. A stress response: The unfolded protein response (UPR)

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 19. Stress responses and checkpoints for DNA damage and replication.