1. + The EGFR Signaling Pathway

2. + EGF Epidermal Growth Factor (EGF) Binds to Epidermal Growth Factor Receptor (EGFR) Results in Cell Growth Cell Proliferation Cell Differentiation Controls through the EGFR signaling pathway

3. + Mouse EGF From Wikipedia

4. + The EGFR Signaling Pathway Overview

5. + The EGFR Signaling Pathway Binds to EGF Controls: signaling adapter proteins: accessory proteins, lack intrinsic enzymatic activity, mediate specific protein-protein interactions that drive the formation of protein complexes Grb2 Shc Enzyme PLC Υ Guanine nucleotide exchange factor: Sos Overview

6. + The EGFR Signaling Pathway Molecules EGF R: Unbounded EGFR Ra: Bounded EGFR R2: Dimeric EGFR Reactions 1. EGF binds to monomeric EGFR 2. EGF-bounded EGFRs dimerize Binding of EGF

7. + The EGFR Signaling Pathway # Ligand-receptor binding egfr(l,r) + egf(r) egfr(l!1,r).egf(r!1) kp1, km1 # Receptor-aggregation egfr(l!1,r) + egfr(l!2,r) egfr(l!1,r!3).egfr(l!2,r!3) kp2,km2 Binding of EGF

8. + The EGFR Signaling Pathway Molecules R2: Dimeric EGFR RP: Transphosphorylated EGFR Reactions 3. Dimeric EGFR transphosphorylation 4. Dimeric EGFR dephosphorylation Transphosphorylation of EGFR

9. + The EGFR Signaling Pathway # Transphosphorylation of egfr egfr(r!1,Y1068~Y) -> egfr(r!1,Y1068~pY) kp3 egfr(r!1,Y1148~Y) -> egfr(r!1,Y1148~pY) kp3 #Dephosphorylayion egfr(Y1068~pY) -> egfr(Y1068~Y) km3 egfr(Y1148~pY) -> egfr(Y1148~Y) km3 Transphosphorylation of EGFR

10. + The EGFR Signaling Pathway Not Included in the BNGL File Molecules PLC Υ PLC Υ P: Phosphorylated PLC Υ RP: EGFR transphosphorylated at Y992 Reactions 5. Binding of PLC Υ 6. Phosphorylation of PLC Υ 7. Binding of PLC Υ P to RP at Y992 Binding of PLC γ

11. + The EGFR Signaling Pathway Molecules Grb2 RP: EGFR transphosphorylated at Y1068 Reactions 9. Binding of Grb2 to RP at Y1068 10. Binding of Sos to pY1068-Grb2 11. Binding of PLC Υ P to RP at 1068 Binding of Grb2

12. + The EGFR Signaling Pathway # Y1068 activity egfr(Y1068~pY) + Grb2(SH2,SH3) egfr(Y1068~pY!1).Grb2(SH2!1,SH3) kp9,km9 egfr(Y1068~pY) + Grb2(SH2,SH3!2) egfr(Y1068~pY!1).Grb2(SH2!1,SH3!2) kp11,km11 egfr(Y1068~pY!1).Grb2(SH2!1,SH3) + Sos(dom) egfr(Y1068~pY!1).Grb2(SH2!1,SH3!2).Sos(dom!2) kp10,km10 Binding of Grb2

13. + The EGFR Signaling Pathway Molecules Shc ShcP: Phosphorylated Shc RP: EGFR transphosphorylated at Y1148/74 Reactions 13. Binding of Shc to pY1148/74 14. Phosphorylation of Shc 15. Binding of ShcP to pY1148/74 17. Binding of Grb2 to pY1148/74- ShcP Binding of Shc

14. + The EGFR Signaling Pathway # Rule 13 egfr(Y1148~pY) + Shc(PTB,Y317~Y) egfr(Y1148~pY!1).Shc(PTB!1,Y317~Y) kp13,km13 # Rule 14 egfr(r!2,Y1148~pY!1).Shc(PTB!1,Y317~Y) -> egfr(r!2,Y1148~pY!1).Shc(PTB!1,Y317~pY) kp14 # Rule 15 egfr(Y1148~pY) + Shc(PTB,Y317~pY) egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY) kp15,km15 # Rule 17 egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY) + Grb2(SH2,SH3) egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3) kp17,km17 Binding of Shc

15. + The EGFR Signaling Pathway Reactions 18. Binding of ShcP-Grb2 to pY1148/74 19. Binding of Sos to pY1148/74- ShcP-Grb2 20. Binding of ShcP-Grb2-Sos to pY1148/74 24. Binding of Grb2-Sos to pY1148/74-ShcP Binding of Shc

16. + The EGFR Signaling Pathway # Rule 18 egfr(Y1148~pY) + Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3) egfr(Y1148~pY!2).Shc(PTB!2,Y317~pY!1).Grb2(SH2!1,SH3) kp18,km18 # Rule 19, note the pattern matching here Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3) + Sos(dom) Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) kp19,km19 # Rule 20 egfr(Y1148~pY) + Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3!3).Sos(dom!3) egfr(Y1148~pY!2).Shc(PTB!2,Y317~pY!1).Grb2(SH2!1,SH3!3).Sos(dom!3) kp20,km20 # Rule 24 egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY) + Grb2(SH2,SH3!3).Sos(dom!3) egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) kp24,km24 Binding of Shc

17. + The EGFR Signaling Pathway Reactions 12. Binding of Grb2 and Sos 23. Binding of Grb2-Sos to ShcP 22. Binding of ShcP-Grb2 to Sos 21. Binding of ShcP and Grb2 16. Dephoshporylation of ShcP 8. Dephoshphorylation of PLC Υ (Not Included) 25. Inactivation of PLC Υ P (Not Included) Cytosolic Reactions without EGFR

18. + The EGFR Signaling Pathway # Rule 12 Grb2(SH2,SH3) + Sos(dom) Grb2(SH2,SH3!1).Sos(dom!1) kp12,km12 # Rule 23 Shc(PTB,Y317~pY) + Grb2(SH2,SH3!2) Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3!2) kp23,km23 # Rule 22 Shc(PTB,Y317~pY!2).Grb2(SH2!2,SH3) + Sos(dom) Shc(PTB,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) kp22,km22 # Rule 21 Shc(PTB,Y317~pY) + Grb2(SH2,SH3) Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3) kp21,km21 # Rule 16 Shc(PTB,Y317~pY) -> Shc(PTB,Y317~Y) km16 Cytosolic Reactions without EGFR

19. + The EGFR Signaling Pathway Putting all together

20. + The END Thank You! 20