2. Ligand Receptor

3. Cortisol Receptor is located in the cytosol Retinoid Receptors are in the nucleus Target gene in the nucleus Regulation of Transcription Promoter Nucleus: Primary and Secondary Responses Receptor/Ligand Binds to promoter elements in DNA and regulates transcription

4. Promoter Activation of transcription Promoter Inhibition of transcription

6. adenylyl G protein  receptor membrane cytosol extracellular space cyclase GDP ligand GTP ATP cAMP Pi

7. cAMP

8. Regulation of Transcription CREB CRE P

9. Some G protein linked receptors linked to Gq activate Ca 2+ signaling PIP2 plays an important role in Ca 2+ signaling PIP2 PI

10. Cleavage of PIP2 gives rise to Ca influx Gq (PLC  ) ER Calcium channel Ca 2+ PKC

11. Calmodulin is a Ca 2+ receptor that mediates many Calcium responses

12. CAM Kinases mediate most Ca 2+ responses CAM Kinase II

13. Regulation of Transcription CREB CRE P cAMP phosphodiesterase and adenylyl cyclase are regulated by CAM Kinases PKA Ca channels Some CAM Kinases are PKA targets CAM Kinases and PKA common targets Regulation of Phosphorylase Kinase by cAMP and Ca

16. EGF Ligand binding usually causes dimerization of the receptor PP PP Membrane outside of the cell inside of the cell

17. GRB2 P-Tyr binds downstream regulators containing SH2 domains P P PP PLC PI3K SH2 Domain GAP Ras pathway

18. GTP GAP GDP GEF Active Inactive Stimulus Ras superfamily of small GTPases help relay signals from RTKs Downstream Signaling Pathways

21. Mammalian Ras activation GRB2 P P PP PLC PI3K SH2 Domain GAP (DRK) SOS Ras GTP Downstream pathways Drosophila Ras activation

22. MAP Kinase Pathways can be mediated by members of the Ras superfamily Stimulus Usually Ras superfamily

25. GRB2 P P PP PLC PI3K GAP Ca 2+ signaling can be activated by RTKs via PLC  Ca 2+ signaling

26. Cleavage of PIP2 gives rise to Ca influx ER Calcium channel Ca 2+ RTK PLC 

27. GRB2 P P PP PLC PI3K GAP Other signaling pathways Cell survival RTKs can activate PI3-Kinase

28. OHOH OH 1 23 4 5 6 P O O O O - CH2 CH CH2 C O CH2 C O OO CH2 PhosphatidylInositol(PI) PI3K OHOH OH 1 23 4 5 6 P O O O O - CH2 CH CH2 C O CH2 C O OO CH2 PI(3)P PI3 Kinase (PI3K) PI3K + PI4K OHOH OH 1 23 4 5 6 P O O O O - CH2 CH CH2 C O CH2 C O OO CH2 PI(3,4)P2 +PI5K OHOH OH 1 23 4 5 6 P O O O O - CH2 CH CH2 C O CH2 C O OO CH2 Cell Survival Pathways Other Signaling Pathways PI(3,4,5)P2

29. OHOH OH 1 23 4 5 6 P O O O O - CH2 CH CH2 C O CH2 C O OO CH2 PhosphatidylInositol(PI) PI3K OHOH OH 1 23 4 5 6 P O O O O - CH2 CH CH2 C O CH2 C O OO CH2 PI(3)P PI3 Kinase (PI3K) and cell survival pathways PI3K + PI4K OHOH OH 1 23 4 5 6 P O O O O - CH2 CH CH2 C O CH2 C O OO CH2 PI(3,4)P2 +PI5K OHOH OH 1 23 4 5 6 P O O O O - CH2 CH CH2 C O CH2 C O OO CH2 PI(3,4,5)P2 AKT PH PH PDK1 P SER BAD ser

30. AKT PI3K - AKT - Cell Survival

31. PP Membrane outside of the cell inside of the cell Tyrosine Kinase (TK) Associated Receptors LIGAND PP

32. Src binds to receptors with and without Tyr Kinase activity Schwartzberg (1998) 17; 1463

33. GRB2 P P PP PLC PI3K Src Cell proliferation, Gene expression, …

34. receptors PP LIGAND