1. CHAPTER 5 Growth Factors, Receptors, and Cancer The human EGF receptor (HER) signaling network.

2. Normal metazoan ( 後生動物 ) cells control each other’s lives Maintenance of tissue architecture.

3. Storage of PDGF by platelets Effects of growth factors on cells.

4. The Src protein functions as a tyrosine kinase

5. Actions of protein kinases Substrate specificity of the Src kinase

6. The EGF receptor functions as a tyrosine kinase

7. Structure of tyrosine kinase receptors

9. An altered growth factor receptor can function as an oncoprotein

10. Deregulation of receptor firing

12. A growth factor gene can become an oncogene: the case of sis

13. Transphosphorylation underlies the operations of receptor tyrosine kinases Formation of phosphotyrosine on the EGFR following ligand addition Apparent autophosphorylation of EGFR 32 PO 4

14. Receptor dimerization, ligand binding, transphosphorylation and glioblastoma pathogenesis

15. Alternative mechanisms of growth factor-induced receptor dimerization. homodimer triple Back-to-back

16. Gene fusion causing constitutively dimerized receptors

17. Multiple structural alterations affect Kit receptor firing. GIST: gastrointestinal stromal tumor AML: acute myelogenous leukemia Kit receptor

18. Yet other types of receptors enable mammalian cells to communicate with their environment Structure of cytokine receptors. Structure of the TGF-  receptor Jaks (Janus kinases) Noncovalently attached

19. Structure of the Notch receptor Two successive proteolytic cleavages

20. The Patched-Smoothened signaling system Trapping Gli

21. Canonical Wnt signaling via Frizzled receptors

22. Non-canonical Wnt signaling via Frizzled receptors

23. Nuclear receptors sense the presence of low–molecular– weight lipophilic ligands Steroid sex hormones, retinoids, vitamin D Estrogen, progesterone and androgen RXR (retinoid X receptor) PPAR-  (peroxisome proliferator-activated receptor-  ) DES (E2 mimic diethylstibestrol) Co-activators Co-repressors

24. Extracellular matrix Glycoprotein, hyaluronan and proteoglycans

25. Integrin receptors sense association between the cell and the extracellular matrix Mg 2+, Mn 2+, Ca 2+  2  1 integrin- collagen I

27. Integrin tethering to the ECM and cytoskeleton Focal adhersion Actin fiber Intermediary protein

28. Some integrins are essential for tumorigenesis

29. The Ras protein, an apparent component of the downstream signaling cascade, functions as a G protein

30. The structure of the Ras protein and its response to GTP binding.

31. Alternative mechanisms of transformation by Ras. 5 min after EGF is added