Fragmenting the early EGFR pathway

Jérôme Feret

Description

Niveau: Supérieur, Licence, Bac+1
Fragmenting the early EGFR pathway Jerome Feret February 16, 2011 All along this pratical work, by “fragments”, we mean homogeneous frag- ments (ie. the fragments which can be generated from a non oriented contact map). Heterogeneous fragments are not implemented yet. 1 The model We consider the following rule set: r01: EGF ( r1 ) , EGFR ( l1,r ) ?? EGF (r ) , EGFR(l ,r ) r02: EGF (r ) , EGFR(l ,r ) ?? EGF ( r1 ) , EGFR ( l1,r ) r03: EGF ( r2 ) , EGF ( r1 ) , EGFR ( l2,r ) , EGFR ( l1,r ) ?? EGF ( r3 ) , EGF ( r2 ) , EGFR ( l3,r1 ) , EGFR ( l2,r1 ) r04: EGF ( r3 ) , EGF ( r2 ) , EGFR ( l3,r1 ) , EGFR ( l2,r1 ) ?? EGF ( r2 ) , EGF ( r1 ) , EGFR ( l2,r ) , EGFR ( l1,r ) r05: EGF ( r3 ) , EGF ( r2 ) , EGFR ( l3,r1 ) , EGFR ( Y68u,l 2,r1 ) ?? EGF ( r3 ) , EGF

• fragment


• egfr


• reset-all


• contact map given


• final time


• annotated contact map


• contact map


• kappa rule


• output-scheme egfr

Sujets

• Fragment

Informations

• Publié par: profil-ontoe-2012
• Nombre de lectures: 49
• Langue: English

Extrait

Fragmenting the early EGFR pathway

J´erˆomeFeret

February 16, 2011

All along this pratical work, by “fragments”, we mean homogeneous frag- ments (ie. the fragments which can be generated from a non oriented contact map). Heterogeneous fragments are not implemented yet.

1Themodel

We consider the following rule set:    1 1 r01:EGF r,EGFR l,r−→EGF(r) ,EGFR(l,r)    1 1 r02:EGF(r) ,EGFR(l,r)−→EGF r,EGFR l,r        2 12 13 2 r03:EGF r,EGF r,EGFR l,r,EGFR l,r−→EGF r,EGF r,    3 12 1 EGFR l,r,EGFR l,r        3 23 12 12 1 r04:EGF r,EGF r,EGFR l,r,EGFR l,r−→EGF r,EGF r,    2 1 EGFR l,r,EGFR l,r       3 23 12 13 r05:EGF r,EGF r,EGFR l,r,EGFR Y68,l,r−→EGF r, u     2 31 21 EGF r,EGFR l,r,EGFR Y68,l,r p   r06:EGFR Y68−→EGFR(Y68) p u       3 23 12 13 r07:EGF r,EGF r,EGFR l,r,EGFR Y48,l,r−→EGF r, u     2 31 21 EGF r,EGFR l,r,EGFR Y48,l,r p   r08:EGFR Y48−→EGFR(Y48) p u      1−1 1−1 r09:EGFR Y48,r,SHC Y7,pi−→EGFR Y48,r,SHC Y7,pi p up p   − − r10:SHC Y7,pi−→SHC(Y7,pi) p u   r11:SHC Y7,pi−→SHC(Y7,pi) p u     1 1 r12:EGFR Y68,GRB2(a,b)−→EGFR Y68,GRB2 a,b p p     1 1 r13:EGFR Y68,GRB2 a,b−→EGFR Y68,GRB2(a,b) p p     −1 1− r14:EGFR Y68,GRB2(a,b)−→EGFR Y68,GRB2 a,b p p     1 1− − r15:EGFR Y68,GRB2 a,b−→EGFR Y68,GRB2(a,b) p p      1 12 21 r16:EGFR Y68,GRB2 a,b,SOS(d)−→EGFR Y68,GRB2 a,b, p p   1 SOS d       2 21 11 1 r17:EGFR Y68,GRB2 a,b,SOS d−→EGFR Y68,GRB2 a,b, p p SOS(d)    1 1 r18:GRB2(a,b) ,SOS(d)−→GRB2 a,b,SOS d    1 1 r19:GRB2 a,b,SOS d−→GRB2(a,b) ,SOS(d)      1 12 12 r20:GRB2 a,b,SHC Y7,pi,SOS(d)−→GRB2 a,b,SHC Y7,pi, p p   1 SOS d

      2 12 11 1 r21:GRB2 a,b,SHC Y7,pi,SOS d−→GRB2 a,b,SHC Y7,pi, p p SOS(d)      1 1−22 1− r22:GRB2 a,b,SHC Y7,pi,SOS(d)−→GRB2 a,b,SHC Y7,pi, p p   1 SOS d       2 12−1 11− r23:GRB2 a,b,SHC Y7,pi,SOS d−→GRB2 a,b,SHC Y7,pi, p p SOS(d)     1 1 r24:EGFR Y48,SHC(Y7,pi)−→EGFR Y48,SHC Y7,pi p up u     1 1 r25:EGFR Y48,SHC Y7,pi−→EGFR Y48,SHC(Y7,pi) p up u      1 1 r26:EGFR Y48,SHC Y7,pi−→EGFR Y48,SHC Y7,pi p pp p      1 1 r27:EGFR Y48,SHC Y7,pi−→EGFR Y48,SHC Y7,pi p pp p       1 12 1 r28:EGFR Y48,GRB2 a,b,SHC Y7,pi−→EGFR Y48,GRB2 a,b, p pp   1 2 SHC Y7,pi p       2 11 21 r29:EGFR Y48,GRB2 a,b,SHC Y7,pi−→EGFR Y48,GRB2 a,b, p pp   1 SHC Y7,pi p       2 12 13 r30:EGFR Y48,GRB2 a,b,SHC Y7,pi,SOS d−→EGFR Y48, p pp     2 12 31 GRB2 a,b,SHC Y7,pi,SOS d p       3 21 23 1 r31:EGFR Y48,GRB2 a,b,SHC Y7,pi,SOS d−→EGFR Y48, p pp     2 12 1 GRB2 a,b,SHC Y7,pi,SOS d p      1 12 1 r32:EGFR Y48,GRB2(a,b) ,SHC Y7,pi−→EGFR Y48,GRB2 a,b, p pp   1 2 SHC Y7,pi p      2 11 21 r33:EGFR Y48,GRB2 a,b,SHC Y7,pi−→EGFR Y48,GRB2(a,b) , p pp   1 SHC Y7,pi p     1 1 r34:GRB2(a,b) ,SHC Y7,pi−→GRB2 a,b,SHC Y7,pi p p     1 1 r35:GRB2 a,b,SHC Y7,pi−→GRB2(a,b) ,SHC Y7,pi p p     −1−1 r36:GRB2(a,b) ,SHC Y7,pi−→GRB2 a,b,SHC Y7,pi p p     1−1− r37:GRB2 a,b,SHC Y7,pi−→GRB2(a,b) ,SHC Y7,pi p p       2 12 13 r38:EGFR Y48,GRB2 a,b,SHC Y7,pi,SOS d−→EGFR Y48, p pp     2 12 31 GRB2 a,b,SHC Y7,pi,SOS d p       3 21 23 12 r39:EGFR Y48,GRB2 a,b,SHC Y7,pi,SOS d−→EGFR Y48, p pp     1 21 GRB2 a,b,SHC Y7,pi,SOS d p

We start with the following initial state:

2000∗(EGFR(l,r,Y48,Y68)) u u 2000∗(EGF(r)) 2000∗(GRB2(a,b)) 1000∗(SOS(d)) 1000∗(SHC(pi,Y7)) u

2

2Firstintuitionsaboutthemodel

(i)Compute the contact map for this model.

In this model, some receptorsEGFRrecruit some proteinsSOS. This can be done in two different ways:

–a receptorEGFRcan be bound to a proteinGRB2that is bound to a protein SOS (short arm); –a receptorEGFRcan be bound to a proteinSHCthat is bound to a protein GRB2, that is bound to a proteinSOS (long arm).

(ii)Compute thestoriesthat describe how a receptorEGFRcan recruit a proteinSOS. (iii)Compute the number of reachable species. (iv)Is it possible for a receptorEGFRto be bound to another receptorEGFR while not being bound to a ligandEGF?

3 Internalcoarse graining

(i)Use the software to compute the reduced differential systems that is associ- ated with our rule set. How many fragments are there? hint:complx egfr.ka --reset-all --do-ODE --output-scheme egfr --final-time 6 (ODE files have the prefixegfr plx ODE). (ii)Argue that the ruler04can be replaced with a simpler rule without modi- fying the behaviour of the model. (iii)Use the software to compress the rule set. hint:complx --reset-all --compute-quantitative-compression egfr.ka --output-quantitative-compression egfrcompressed.ka (iv)Explain the kinetic factor of the ruler04in the compressed rule set. (v)Use the software to compute the reduced differential systems that is associ- ated with compressed rule set. How many fragments are there?

The reduction used the annotated contact map that is given in Fig. 1.

(vi)Motivate each solid/strong edge and each covering class. (vii)Which subspecies in Fig. 2 are fragments with respect to the annotated contact map given Fig. 1 ? (viii)Explain why, with the initial rule set, the edge between the siterof the agentEGFRand itself, should be solid/strong. (ix)Plot the concentration of the proteinsSOSthat are attached to a receptor according to the simulation time. hint:Use eitherOctaveorMatlabto run the fileegfr plx ODE system.m. It will generate the filesegfr plx.data,egfr plx head.dataandegfr plx ODE.gplot.

3

d

SOS

b

GRB2

a

Y68

EGF

r

l

Y7 GFR Y48 p

SHC

r

Fig. 1.annotated contact map.

4 Morecomplex example Now, we consider that the bond between a ligandEGFand a receptorEGFR can be broken even if the receptor is bound to another receptor. (i)Encode this assumption as a kappa rule. (ii)How is modified the annotated contact map and the set of fragments? Do you think the reduction that is obtained thanks to the application is optimal?

4

SOS d

GRB2 a b

GRB2 a b SHC Y 7 GRB2SHC a b Y 7

GRB2SHC a b Y 7 pi

Fig. 2.fragment candidates

5