Dataset Information

Fujita2010_Akt_Signalling_EGFRinhib

ABSTRACT: Akt pathway model with EGFR inhibitor made by Kazuhiro A. Fujita. This is the Akt pathway model with an EGFR inhibitor described in: Decoupling of receptor and downstream signals in the Akt pathway by its low-pass filter characteristics. Fujita KA, Toyoshima Y, Uda S, Ozaki Y, Kubota H, and Kuroda S. Sci Signal. 2010 Jul 27;3(132):ra56. PMID: 20664065 ; DOI: 10.1126/scisignal.2000810 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. The different versions of input, step, pulse and ramp, can be simulated using the parameters EGF_conc_pulse , EGF_conc_step and EGF_conc_ramp . Depending on which one is set unequal to 0, either a continous pulse with value EGF_conc_pulse , a 60 second step with EGF_conc_step or a signal increasing from 0 to EGF_conc_pulse over a time periode of 3600 seconds are used as input. In case more than one parameter are set to values greater than 0 these input profiles are added to each other. The pulse time and the time over which the ramp input increases can be set by pulse_time and ramp_time . This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels Team. For more information see the terms of use . To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

SUBMITTER: Kazuhiro Fujita

PROVIDER: BIOMD0000000264 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000264?filename=BIOMD0000000264-biopax2.owl	Owl
	BIOMD0000000264?filename=BIOMD0000000264-biopax3.owl	Owl
	BIOMD0000000264?filename=BIOMD0000000264-matlab.m	Other
	BIOMD0000000264?filename=BIOMD0000000264-octave.m	Other
	BIOMD0000000264?filename=BIOMD0000000264.m	Other

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Publications

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

Fujita Kazuhiro A KA Toyoshima Yu Y Uda Shinsuke S Ozaki Yu-ichi Y Kubota Hiroyuki H Kuroda Shinya S

Science signaling 20100727 132

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)-dependen ...[more]

PMID: 20664065

Similar Datasets

Project description:EGF dependent Akt pathway model made by Kazuhiro A. Fujita. This is the EGF dependent Akt pathway model described in: Decoupling of receptor and downstream signals in the Akt pathway by its low-pass filter characteristics. Fujita KA, Toyoshima Y, Uda S, Ozaki Y, Kubota H, and Kuroda S. Sci Signal. 2010 Jul 27;3(132):ra56. PMID: 20664065 ; DOI: 10.1126/scisignal.2000810 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. The different versions of input, step, pulse and ramp, can be simulated using the parameters EGF_conc_pulse , EGF_conc_step and EGF_conc_ramp . Depending on which one is set unequal to 0, either a continous pulse with value EGF_conc_pulse , a 60 second step with EGF_conc_step or a signal increasing from 0 to EGF_conc_pulse over a time periode of 3600 seconds are used as input. In case more than one parameter are set to values greater than 0 these input profiles are added to each other. The pulse time and the time over which the ramp input increases can be set by pulse_time and ramp_time . This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels Team. For more information see the terms of use . To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

Project description:NGF dependent Akt pathway model made by Kazuhiro A. Fujita. This is the NGF dependent Akt pathway model described in: Decoupling of receptor and downstream signals in the Akt pathway by its low-pass filter characteristics. Fujita KA, Toyoshima Y, Uda S, Ozaki Y, Kubota H, and Kuroda S. Sci Signal. 2010 Jul 27;3(132):ra56. PMID: 20664065 ; DOI: 10.1126/scisignal.2000810 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. The different versions of input, step, pulse and ramp, can be simulated using the parameters NGF_conc_pulse , NGF_conc_step and NGF_conc_ramp . Depending on which one is set unequal to 0, either a continous pulse with value NGF_conc_pulse , a 60 second step with NGF_conc_step or a signal increasing from 0 to NGF_conc_pulse over a time periode of 3600 seconds are used as input. In case more than one parameter is set to values greater than 0 these input profiles are added to each other. The pulse time and the time over which the ramp input increases can be set by pulse_time and ramp_time . This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels Team. For more information see the terms of use . To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

Project description:Introduction: The clinical benefit of EGFR tyrosine kinase inhibitor (TKI) treatment in non-small cell lung cancer (NSCLC) patients with activating EGFR mutations is temporary, as virtually all patients develop acquired EGFR TKI resistance that occurs via diverse mechanisms. Here, we identified increased FGFR1 expression as such a resistance mechanism and using pathways analysis and drug combination testing we identified a novel combination treatment to control growth of these resistant tumors. Methods: Novel erlotinib-resistant NSCLC cell lines were generated and analyzed by mass spectrometry-based proteomics to identify altered pathways associated with erlotinib resistance. The altered pathways were further analyzed in gefitinib and osibenib resistant cell lines. Small molecule inhibitor combinations were used to block the altered pathways and investigate growth reduction in vitro and in two xenograft mouse models. FGFR1 mRNA levels were examined in pre- and (post?)- EGFR TKI treatment clinical tumor samples. Results: Proteomic analysis revealed increased expression of FGFR1 and AXL as well as increased Akt and ERK1/2 activation in a panel of novel erlotinib-resistant HCC827 cell lines. Combined treatment with erlotinib or osimertinib and a panel of small molecule inhibitors targeting AXL/MET, FGFRs, Akt, PI3K/mTOR, MEK or ERK1/2 showed that the most prominent re-sensitization to EGFR TKI occurred with the pan-FGFR inhibitor, PD173074. Interestingly, simultaneous blockade of components of the Akt pathway using specific Akt or dual PI3K-mTOR inhibitors combined with inhibitors targeting the FGFR family exhibited the most efficient growth inhibition of FGFR1 overexpressing EGFR TKI-resistant cell lines. Phosphorylation of proteins downstream of Akt, including PRAS40, FOXO and S6 ribosomal protein, were completely abrogated by PD173074 combined with the Akt inhibitor GSK2141795 . Combination treatment with PD173074 and an Akt inhibitor exhibited synergistic growth inhibition in vivo in two FGFR1 overexpressing NSCLC EGFR TKI-resistant animal models. Conclusion: The significant growth inhibition in vitro and in vivo observed with PD173074 combined with Akt compared to either drug alone imply that inhibition of several key targets may be beneficial in controlling erlotinib-resistant NSCLC. The complete abrogation of PRAS40, FOXO and S6 phosphorylations by PD173074 combined with an Akt inhibitor indicates that the Akt pathway is no longer active.