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fujita

fujita

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Reactions

re1

re1

EGFR + EGF > EGF_EGFR

re12

re12

pMEKcyt + ERKcyt > pMEK_ERK_cyt

re15

re15

pTpYERK_cyt > pTpYERK_nuc

re16

re16

ERKcyt > ERKnuc

re2

re2

EGF_EGFR > degra_EGF_pEGFR

re22

re22

pMEKcyt > MEKcyt

re27

re27

RasEffector + Ras_GTP > RassEffector

re28

re28

Sos1_2 > pSos

re3

re3

Sos1_2 + EGF_EGFR > EGFR_Sos

re30

re30

pSos > ppSos

re31

re31

ppSos > pppSos

re32

re32

pppSos > ppppSos

re4

re4

Ras_GDP > Ras_GTP

re42

re42

pMEK_ERK_cyt > pMEK_pYERK

re43

re43

pMEK_pYERK > pMEKcyt + pTpYERK_cyt

re44

re44

pTpYERK_cyt > pTERK_cyt

re45

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pTpYERK_cyt > pYERK_cyt

re46

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pYERK_cyt > ERKcyt

re47

re47

pTERK_cyt > ERKcyt

re48

re48

pYERK_cyt > pTpYERK_cyt

re49

re49

pTERK_cyt > pTpYERK_cyt

re5

re5

Ras_GTP > Ras_GDP

re50

re50

pYERK_cyt > pYERK_nuc

re51

re51

pTERK_cyt > pTERK_nuc

re52

re52

pTpYERK_nuc > pYERK_nuc

re53

re53

pTpYERK_nuc > pTERK_nuc

re54

re54

pYERK_nuc > ERKnuc

re55

re55

pTERK_nuc > ERKnuc

re56

re56

MEKcyt > pMEKcyt

re57

re57

Shoc2 + Ras_GTP > Ras_Shoc2

re58

re58

cRaf + Ras_Shoc2 > Ras_Shoc2_cRaf

re6

re6

cRaf + Ras_GTP > Ras_Raf

re62

re62

PI3K > active_PI3K

re63

re63

Akt > pAkt

re64

re64

TSC > pTSC

re65

re65

Rheb_GTP > Rheb_GDP

re66

re66

S6K > pS6K

re67

re67

RSK > pRSK

re68

re68

cRaf > inactive_cRaf

re69

re69

EGF_EGFR > degra_EGF_pEGFR

re70

re70

inactive_cRaf > cRaf

re9

re9

ERKcyt + MEKcyt > MEK_ERK_cyt

Parameters

Global parameters

Fixed species

Initial values

Functions and Rules

Events

EGFtrig

Trigger: time==6000

Delay: 0

Assignments:

  • EGF = 0.0016

Constraints

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.


Species:

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Decoupling of receptor and downstream signals in the Akt pathway by its low-pass filter characteristics.

  • Kazuhiro A Fujita
  • Yu Toyoshima
  • Shinsuke Uda
  • Yu-ichi Ozaki
  • Hiroyuki Kubota
  • Shinya Kuroda
Sci Signal 2010; 3 (132):
Abstract
In cellular signal transduction, the information in an external stimulus is encoded in temporal patterns in the activities of signaling molecules; for example, pulses of a stimulus may produce an increasing response or may produce pulsatile responses in the signaling molecules. Here, we show how the Akt pathway, which is involved in cell growth, specifically transmits temporal information contained in upstream signals to downstream effectors. We modeled the epidermal growth factor (EGF)-dependent Akt pathway in PC12 cells on the basis of experimental results. We obtained counterintuitive results indicating that the sizes of the peak amplitudes of receptor and downstream effector phosphorylation were decoupled; weak, sustained EGF receptor (EGFR) phosphorylation, rather than strong, transient phosphorylation, strongly induced phosphorylation of the ribosomal protein S6, a molecule downstream of Akt. Using frequency response analysis, we found that a three-component Akt pathway exhibited the property of a low-pass filter and that this property could explain decoupling of the peak amplitudes of receptor phosphorylation and that of downstream effectors. Furthermore, we found that lapatinib, an EGFR inhibitor used as an anticancer drug, converted strong, transient Akt phosphorylation into weak, sustained Akt phosphorylation, and, because of the low-pass filter characteristics of the Akt pathway, this led to stronger S6 phosphorylation than occurred in the absence of the inhibitor. Thus, an EGFR inhibitor can potentially act as a downstream activator of some effectors.

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