+

The EGFR Signaling Pathway

+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

+ Mouse EGF

From Wikipedia

+The EGFR Signaling PathwayOverview

+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 PLCΥ Guanine nucleotide exchange factor: Sos

Overview

+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

+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

+The EGFR Signaling Pathway

Molecules R2: Dimeric EGFR RP: Transphosphorylated

EGFR

Reactions

3. Dimeric EGFR transphosphorylation

4. Dimeric EGFR dephosphorylation

Transphosphorylation of EGFR

+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

+The EGFR Signaling Pathway

Not Included in the BNGL File

Molecules PLCΥ PLCΥP: Phosphorylated PLCΥ RP: EGFR

transphosphorylated at Y992

Reactions

5. Binding of PLCΥ

6. Phosphorylation of PLCΥ

7. Binding of PLCΥP to RP at Y992

Binding of PLCγ

+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 PLCΥP to RP at 1068

Binding of Grb2

+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

+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

+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

+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

+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

+The EGFR Signaling Pathway

Reactions

12. Binding of Grb2 and Sos

23. Binding of Grb2-Sos to ShcP

24. Binding of ShcP-Grb2 to Sos

25. Binding of ShcP and Grb2

26. Dephoshporylation of ShcP

27. Dephoshphorylation of PLCΥ(Not Included)

25. Inactivation of PLCΥP (Not Included)

Cytosolic Reactions without EGFR

+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

+The EGFR Signaling PathwayPutting all together

20

+The ENDThank You!