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The EGFR Signaling Pathway

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 Pathway. Overview.

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The EGFR Signaling Pathway

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  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 PLCΥ Guanine nucleotide exchange factor: Sos Overview

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

  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 Transphosphorylation of EGFR • Molecules • R2: Dimeric EGFR • RP: Transphosphorylated EGFR • Reactions • Dimeric EGFR transphosphorylation • Dimeric EGFR dephosphorylation

  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 Binding of PLCγ • Not Included in the BNGL File • Molecules • PLCΥ • PLCΥP: Phosphorylated PLCΥ • RP: EGFR transphosphorylated at Y992 • Reactions • Binding of PLCΥ • Phosphorylation of PLCΥ • Binding of PLCΥP to RP at Y992

  11. The EGFR Signaling Pathway Binding of Grb2 • Molecules • Grb2 • RP: EGFR transphosphorylated at Y1068 • Reactions • Binding of Grb2 to RP at Y1068 • Binding of Sos to pY1068-Grb2 • Binding of PLCΥP to RP at 1068

  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 Binding of Shc • Molecules • Shc • ShcP: Phosphorylated Shc • RP: EGFR transphosphorylated at Y1148/74 • Reactions • Binding of Shc to pY1148/74 • Phosphorylation of Shc • Binding of ShcP to pY1148/74 • Binding of Grb2 to pY1148/74-ShcP

  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 Binding of Shc • Reactions • Binding of ShcP-Grb2 to pY1148/74 • Binding of Sos to pY1148/74-ShcP-Grb2 • Binding of ShcP-Grb2-Sos to pY1148/74 • Binding of Grb2-Sos to pY1148/74-ShcP

  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 CytosolicReactionswithoutEGFR • Reactions • Binding of Grb2 and Sos • Binding of Grb2-Sos to ShcP • Binding of ShcP-Grb2 to Sos • Binding of ShcP and Grb2 • Dephoshporylation of ShcP • Dephoshphorylation of PLCΥ(Not Included) • Inactivation of PLCΥP (Not Included)

  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!

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