EGFR

Report
+
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
+
The EGFR Signaling Pathway
Overview

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
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The EGFR Signaling Pathway
Binding of EGF


Molecules

EGF

R: Unbounded EGFR

Ra: Bounded EGFR

R2: Dimeric EGFR
Reactions
1.
EGF binds to monomeric EGFR
2.
EGF-bounded EGFRs dimerize
+
The EGFR Signaling Pathway
Binding of EGF
# 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
+
The EGFR Signaling Pathway
Transphosphorylation of EGFR


Molecules

R2: Dimeric EGFR

RP: Transphosphorylated EGFR
Reactions
3.
Dimeric EGFR
transphosphorylation
4.
Dimeric EGFR
dephosphorylation
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The EGFR Signaling Pathway
Transphosphorylation of EGFR
# 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
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The EGFR Signaling Pathway
Binding of PLCγ

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
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The EGFR Signaling Pathway
Binding of Grb2


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
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The EGFR Signaling Pathway
Binding of Grb2
# 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
+
The EGFR Signaling Pathway
Binding of Shc

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 pY1148/74ShcP
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The EGFR Signaling Pathway
Binding of Shc
# 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
+
The EGFR Signaling Pathway
Binding of Shc

Reactions
18.
Binding of ShcP-Grb2 to
pY1148/74
19.
Binding of Sos to pY1148/74ShcP-Grb2
20.
Binding of ShcP-Grb2-Sos to
pY1148/74
24.
Binding of Grb2-Sos to
pY1148/74-ShcP
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The EGFR Signaling Pathway
Binding of Shc
# 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
+
The EGFR Signaling Pathway
Cytosolic Reactions without EGFR

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 PLCΥ(Not
Included)
25.
Inactivation of PLCΥP (Not
Included)
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The EGFR Signaling Pathway
Cytosolic Reactions without EGFR
# 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
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The EGFR Signaling Pathway
Putting all together
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The END
Thank You!
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