Cellière2011 - Plasticity of TGF-β Signalling

Transforming growth factor beta (TGF-β) signalling has been implicated as an important regulator of almost all major cell behaviours, including proliferation, differentiation, cell death, and motility. It remains unclear that how the TGF-β signalling pathway accomplishes the flexibility in its responses. What and how many parameters have to be altered for cells to respond differently to perform complex tasks? This canonical response has been explored in this model, by considering the core signalling architecture of TGF-β pathway.

This model is described in the article:

Plasticity of TGF-β signaling
Cellière G, Fengos G, Hervé M, Iber D.
BMC Syst Biol. 2011 Nov 3;5:184.

Abstract:

The family of TGF-β ligands is large and its members are involved in many different signaling processes. These signaling processes strongly differ in type with TGF-β ligands eliciting both sustained or transient responses. Members of the TGF-β family can also act as morphogen and cellular responses would then be expected to provide a direct read-out of the extracellular ligand concentration. A number of different models have been proposed to reconcile these different behaviours. We were interested to define the set of minimal modifications that are required to change the type of signal processing in the TGF-β signaling network. RESULTS: To define the key aspects for signaling plasticity we focused on the core of the TGF-β signaling network. With the help of a parameter screen we identified ranges of kinetic parameters and protein concentrations that give rise to transient, sustained, or oscillatory responses to constant stimuli, as well as those parameter ranges that enable a proportional response to time-varying ligand concentrations (as expected in the read-out of morphogens). A combination of a strong negative feedback and fast shuttling to the nucleus biases signaling to a transient rather than a sustained response, while oscillations were obtained if ligand binding to the receptor is weak and the turn-over of the I-Smad is fast. A proportional read-out required inefficient receptor activation in addition to a low affinity of receptor-ligand binding. We find that targeted modification of single parameters suffices to alter the response type. The intensity of a constant signal (i.e. the ligand concentration), on the other hand, affected only the strength but not the type of the response. CONCLUSIONS: The architecture of the TGF-β pathway enables the observed signaling plasticity. The observed range of signaling outputs to TGF-β ligand in different cell types and under different conditions can be explained with differences in cellular protein concentrations and with changes in effective rate constants due to cross-talk with other signaling pathways. It will be interesting to uncover the exact cellular differences as well as the details of the cross-talks in future work.

This model is hosted on BioModels Database and identified by: MODEL1208280000 .

To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. 20587024 .

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to [CC0 Public Domain Dedication>http://creativecommons.org/publicdomain/zero/1.0/] for more information.

 4.0 SQUARE SQUARE inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive 2015-11-23T13:34:20Z Juty Nick juty@ebi.ac.uk EMBL-EBI Fengos Georgios georgios.fengos@bsse.ethz.ch Eidgenössische Technische Hochschule Zurich (ETHZ) Struck Travis tjstruck@email.arizona.edu University of Arizona Davison Dinah dinahdavison@email.arizona.edu University of Arizona Zaepfel Benjamin benzaepfel@email.arizona.edu University of Arizona Wellington Rachel rwellington@email.arizona.edu University of Arizona Gutenkunst Ryan rgutenk@email.arizona.edu University of Arizona Chelliah Vijayalakshmi viji@ebi.ac.uk EMBL-EBI 2016-04-18T12:54:50Z 2016-04-18T14:56:39Z 2015-12-01T15:53:33Z Smad_P_CoSmad_N h k14 k15 k14 Smad_P_CoSmad_N h Smad_P_CoSmad_N h k15 h 2015-12-01T15:42:56Z Smad_P_Smad_P k12 k8 k12 k8 Smad_P_Smad_P 2015-12-01T15:51:57Z I_Smad_mRNA2 k18 k18 I_Smad_mRNA2 2015-12-01T17:01:23Z k7 Smad TGFb_TGFbR_P k7 Smad TGFb_TGFbR_P 
Defined by provided Gene Ontology annotation.
 cytoplasm 2015-12-01T11:44:09Z 
Gene Ontology GO:0005634 encompasses the term information for the nucleus compartment of the cell.
 nucleus 2015-12-01T11:44:12Z 
Defined by provided Gene Ontology annotation.
 2015-12-01T19:11:50Z 
Authors specified the receptor in the model is TGF-Beta type 1 receptor.
 inside PROTEIN pr1 2015-12-01T11:53:47Z 
A complex of a ligand withing the TGF-Beta family and TGF-Beta type 1 receptor.

The authors did not specify the exact ligand that they wanted in their model and only refered to it as TGF-Beta. They do specify that the receptor is type 1.
 inside PROTEIN pr2 2015-12-03T09:07:27Z 
A complex of a ligand withing the TGF-Beta family and TGF-Beta type 1 receptor.

Receptor is phosphorylated.

The authors did not specify the exact ligand that they wanted in their model and only refered to it as TGF-Beta. They do specify that the receptor is type 1.
 inside PROTEIN pr3 2015-12-06T12:10:05Z 
This complex consists of an inhibitory Smad with a SMAD domain, a TGF-beta ligand and a phosphorylated TGF-beta receptor.
 inside PROTEIN pr4 The regulation of inhibitory Smads promotes bone morphometric protein signaling. 2015-12-01T11:53:33Z 
InterPro annotation gives details on and source information for general Smads (including R-Smad). 

GeneOntology GO:0070412 reference outlines terms associated with R-Smad binding, which is the major element associated with this reaction.

Gene Ontology GO:0010862 reference outlines terms associated with SMAD protein phosphorylation, a critical element of setting up SMAD_P elements.

Most annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 inside PROTEIN pr5 2015-12-01T11:58:55Z 
InterPro annotation gives details on and source information for general Smads (including R-Smad and Co-Smad, as utilized in this reaction). 

GeneOntology GO:0070412 reference outlines terms associated with R-Smad binding, which is the major element associated with this reaction.

Gene Ontology GO:0010862 reference outlines terms associated with SMAD protein phosphorylation, a critical element of setting up SMAD_P elements.

Most annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 inside PROTEIN pr6 2015-12-06T11:54:06Z 
Annotation provides information on the general Smad family.
 inside PROTEIN pr7 2015-12-01T11:44:40Z 
Phosphorylated version of Smad 2 or 3 complex (either homomer or heteromer).

Localized to the cytoplasm.

The authors were interested in Smad 2 and 3, since they are involved in the TGF-Beta pathway. So this any combination of the Smads binding to form a homodimer (ex. Smad 2 dimerizing with anouther Smad 2 molecule) or a heterodimer of Smad 2 and Smad 3.
 inside PROTEIN pr8 2015-12-06T12:09:59Z 
InterPro annotation gives details on and source information for general Smads (including R-Smad and Co-Smad, as utilized in this reaction). 

GeneOntology GO:0070412 reference outlines terms associated with R-Smad binding, which is the major element associated with this reaction.

Gene Ontology GO:0010862 reference outlines terms associated with SMAD protein phosphorylation, a critical element of setting up SMAD_P elements.

Gene Ontology GO:0070410 references outlines terms associated with Co-Smad binding, a major element in this reaction.

Uniprot Q13485 is a Homo sapien version of Smad4, the Smad indicated as a Co-Smad used by the model authors.

Most annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 inside PROTEIN pr9 2015-12-06T11:55:51Z 
Annotation provides information on the general Smad family.

mRNA coding for I_Smad localized to the cytoplasm.
 inside PROTEIN pr16 2015-12-01T17:07:48Z 
Annotation provides information on the general Smad family.
 inside PROTEIN pr17 2015-12-01T19:11:55Z 
InterPro annotation gives details on and source information for general Smads (including R-Smad). 

GeneOntology GO:0070412 reference outlines terms associated with R-Smad binding, which is the major element associated with this reaction.

Gene Ontology GO:0010862 reference outlines terms associated with SMAD protein phosphorylation, a critical element of setting up SMAD_P elements.

Most annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 inside PROTEIN pr10 2015-12-06T11:48:38Z 
Phosphorylated version of Smad 2 or 3 complex (either homomer or heteromer).

Localized to the nucleus.

The authors were interested in Smad 2 and 3, since they are involved in the TGF-Beta pathway. So this any combination of the Smads binding to form a homodimer (ex. Smad 2 dimerizing with anouther Smad 2 molecule) or a heterodimer of Smad 2 and Smad 3.
 inside PROTEIN pr11 2015-12-03T09:07:02Z 
InterPro annotation gives details on and source information for general Smads (including R-Smad and Co-Smad, as utilized in this reaction). 

GeneOntology GO:0070412 reference outlines terms associated with R-Smad binding, which is the major element associated with this reaction.

Gene Ontology GO:0010862 reference outlines terms associated with SMAD protein phosphorylation, a critical element of setting up SMAD_P elements.

Most annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 inside PROTEIN pr12 2015-12-01T19:12:20Z 
InterPro annotation gives details on and source information for general Smads (including R-Smad and Co-Smad, as utilized in this reaction). 

GeneOntology GO:0070412 reference outlines terms associated with R-Smad binding, which is the major element associated with this reaction.

Gene Ontology GO:0010862 reference outlines terms associated with SMAD protein phosphorylation, a critical element of setting up SMAD_P elements.

Gene Ontology GO:0070410 references outlines terms associated with Co-Smad binding, a major element in this reaction.

Uniprot Q13485 is a Homo sapien version of Smad4, the Smad indicated as the Co-Smad used by the model authors.

Most annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 inside PROTEIN pr13 2015-12-06T12:01:49Z 
Annotation provides information on the general Smad family.

CoSmad localized to the nucleus.
 inside PROTEIN pr14 2015-12-06T11:54:26Z 
Annotation provides information on the general Smad family.

mRNA coding for I_Smad localized to the nucleus.
 inside PROTEIN pr15 2015-12-01T17:07:35Z 
TGF-Beta ligand.

Pulled from the paper Constraint-based modeling and kinetic analysis of the Smad dependent TGF-beta signaling pathway.

Deviated from published value.
 2015-12-01T16:53:05Z 
Assigned the range 1 to 4 by the authors.

No data from previous literature, values were estimated.
 2015-12-03T09:11:52Z 
Assigned the range 10e-5 to 10e-2 by the authors.

Data obtained from provided literature.
 2015-12-03T09:12:14Z 
k2 describes the rate of TGFb binding with TGFbR.

Assigned the range of 10E-7 to 10E-3 by the model authors. This range encompasses the reported values from the annotated references.
 2015-12-03T09:12:48Z 
k3 describes the rate of phosphorylation of TGFb:TGFbR.

Assigned the range of 10E-3 to 1 by the model authors as there were no previously reported parameter values.
 2015-12-03T09:13:09Z 
k4 describes the rate of dephosphorylation of TGFb:TGFbR.

Assigned the range of 10E-3 to 1 by the model authors as there were no previously reported parameter values.
 2015-12-03T09:13:42Z 
Assigned the range 10e-7 to 10e-5 by the authors.

Data obtained from provided literature.
 2015-12-03T09:14:51Z 
Rate of nuclear import.

Pulled from the paper Mathematical modeling identifies Smad nucleocytoplasmic shuttling as a dynamic signal-interpreting system.

Pulled from the paper Quantitative modeling and analysis of the transforming growth factor beta signaling pathway.

Pulled from the paper Systems theory of Smad signalling.
 2015-12-03T09:15:09Z 
Rate of nuclear export.

Pulled from the paper Mathematical modeling identifies Smad nucleocytoplasmic shuttling as a dynamic signal-interpreting system.

Pulled from the paper Quantitative modeling and analysis of the transforming growth factor beta signaling pathway.

Pulled from the paper Systems theory of Smad signalling.
 2015-12-01T16:53:01Z 
Assigned the range 10e-8 to 10e-4 by the authors.

Data obtained from provided literature.
 2015-12-03T09:12:39Z 
Assigned the range 10e-4 to 1 by the authors.

Data obtained from provided literature.
 2015-12-03T09:16:07Z 
Assigned the range 10e-2 to 10 by the authors.

Data obtained from provided literature.
 2015-12-03T09:16:20Z 
Assigned the range 10e-3 to 10e-1 by the authors.

Data obtained from provided literature.
 2015-12-03T09:16:36Z 
k5 describes the rate at which TGFb:TGFbR_P associates into a TGFb:TGFbR:I-Smad complex.

Assigned the range of 10E-4 to 1 by the model authors as there were no previously reported parameter values.
 2015-12-03T09:12:09Z 
k6 describes the rate of TGFb:TGFbR dissociation from its complex with I-Smad.

Assigned the range of 10E-6 to 1 by the model authors as there were no previously reported parameter values.
 2015-12-03T09:14:31Z 
Nuclear Smad/Co-Smad complexes trigger transcription of I-Smad mRNA. The I-Smad expression rate was varied over 5 orders of magnitude by the authors to determine the appropriate value for the model. Annotations are for the regulation of gene expression, the Smad complex which binds to chromatin and the SMAD domain, which the I-Smad mRNA codes for.
 How the Smads regulate transcription. 2015-12-03T09:16:57Z 
k15 describes the phosphorylated Smad/Co-Smad complex binding to chromatin and facilitating gene transcription, particularly the transcription of I-Smad. The I-Smad expression rate was varied over 5 orders of magnitude by the authors to determine the appropriate value for the model. Annotations are for the regulation of gene expression, the Smad complex which binds to chromatin and the SMAD domain, which the I-Smad mRNA codes for.
 How the Smads regulate transcription. 2015-12-03T09:17:11Z 
k16 describes the shuttling of inhibitory Smad mRNA from the nucleus to the cytoplasm. Annotations are for nuclear export and for the SMAD domain, which is encoded by the I-Smad mRNA.
 Smad transcription factors and translation. 2015-12-01T15:43:11Z 
k17 describes the degradation of inhibitory Smad mRNA. Annotations are for the SMAD domain, which is encoded by the I-Smad mRNA, and for an mRNA catabolic process.
 Smad transcription factors and translation. 2015-12-03T09:17:51Z 
k18 describes the translation of inhibitory Smad mRNA, a component of the TGF-beta signaling pathway. This is annotated with the SMAD domain.
 Smad transcription factors and translation. 2015-12-03T09:18:02Z 
k19 describes the rate of degradation of I-Smad in the cytoplasm.

Assigned the range of 10E-5 to 10E-1 by the model authors as there were no previously reported parameter values.
 2015-12-03T09:18:16Z 
This reaction represents dissociation of the ligand TGF-beta from the TGF-beta receptor.
 r1 STATE_TRANSITION 2015-12-01T11:49:05Z c k1 TGFb_TGFbR 
TGF-beta binds to the TGF-beta receptor. Annotations are for TGF-beta receptor binding, the TGF-beta family and the TGF-beta receptor family.
 r2 STATE_TRANSITION The high-affinity binding of TGF-beta to the type II TGF-beta receptor. 2015-12-01T14:20:59Z k2 TGFbR TGFb 
Phosphorylation of TGF-Beta type 1 receptor bound to TGF-Beta by protein serine/threonine kinase activity.
 r3 STATE_TRANSITION 2015-12-01T14:22:30Z c k3 TGFb_TGFbR 
Dephosphorylation of TGF-Beta type 1 receptor bound to TGF-Beta.
 r4 STATE_TRANSITION 2015-12-01T14:22:54Z c k4 TGFb_TGFbR_P 
I-Smad sequestering and dephosphorylating TGF-Beta type 1 receptor.
 r5 STATE_TRANSITION 2015-12-01T14:23:22Z c k5 TGFb_TGFbR_P I_Smad 
I-Smad and TGF-Beta type 1 receptor dissociate from each other.
 r6 STATE_TRANSITION 1.795935659479886E-4,0.0818716412549444 1.0003934235041092,0.07978107149501928 2015-12-01T14:23:42Z c k6 I_Smad_TGFb_TGFbR_P 
Phosphorylation of Smad 2 or Smad 3.
 r7 STATE_TRANSITION 2015-12-01T14:24:01Z c Function_for_r7__1 k7 Smad TGFb_TGFbR_P 
Unphosphorylated Smad 2 or Smad 3 import into the nucleus.
 r8 STATE_TRANSITION 2015-12-01T14:25:30Z k8 Smad 
Unphosphorylated Smad 2 or Smad 3 export from the nucleus.
 r9 STATE_TRANSITION 2015-12-01T14:25:52Z k9 Smad_N 
Smad_P represents phosphorylated Smad.

Smad_P_Smad_P represents a homodimer of phosporylated Smads.

This reaction represents homodimerization of phosphorylated Smads.
 r10 STATE_TRANSITION 0.7111663883396115,-0.44518540774331594 2015-12-01T11:47:03Z c k10 Smad_P 2 
Smad_P represents phosphorylated Smad.

Smad_P_Smad_P represents a homodimer of phosporylated Smads.

This reaction represents dissociation of the homodimer Smad_P_Smad_P into two phosphorylated Smads.
 r11 STATE_TRANSITION 0.2739970545263599,0.43689022918826637 2015-12-01T11:49:04Z c k11 Smad_P_Smad_P 
Smad_P represents phosphorylated Smad.

Smad_P_CoSmad represents the heterodimer containing Smad_P and CoSmad.

This reaction represents the binding of Smad_P and CoSmad to form the heterodimer Smad_P_CoSmad.
 r12 STATE_TRANSITION 0.8805364705741345,-0.3171374141710883 2015-12-01T11:49:03Z c k10 Smad_P CoSmad 
Smad_P represents phosphorylated Smad.

Smad_P_CoSmad represents the heterodimer containing Smad_P and CoSmad.

This reaction represents the dissociation of the Smad_P_CoSmad heterodimer into Smad_P and CoSmad.
 r13 STATE_TRANSITION 0.11134133191623885,0.3066908700065112 2015-12-01T11:47:01Z c k11 Smad_P_CoSmad 
CoSmad_N represents CoSmad located in the nucleus.

This reaction represents the transport of CoSmad to the nucleus from the cytoplasm.
 r14 STATE_TRANSITION 2015-12-01T11:49:02Z k8 CoSmad 
CoSmad_N represents CoSmad located in the nucleus.

This reaction represents the transport of CoSmad from the nucleus to the cytoplasm.
 r15 STATE_TRANSITION 2015-12-01T11:49:00Z k9 CoSmad_N 
The phosphorylated Smad complex is shuttled into the nucleus. GO annotation corresponds to Smad protein import into nucleus.
 r16 STATE_TRANSITION TGF-beta signaling mechanisms. Smad protein shuttling between the nucleus and the cytoplasm. 2015-12-01T11:46:19Z Function_for_r16__1 Smad_P_Smad_P k12 k8 
Phosphorylated Smad is shuttled into the nucleus. Annotations correspond to the SMAD domain (contained within the phosphorylated Smad) and the activity of nuclear shuttling.
 r17 STATE_TRANSITION Smad protein shuttling between the nucleus and the cytoplasm. 2015-12-01T11:46:57Z k8 Smad_P 
Phosphorylated Smad is shuttled from the nucleus and the cytoplasm. Annotations are for the SMAD domain present within the phosphorylated Smad and nuclear export.
 r18 STATE_TRANSITION Smad protein shuttling between the nucleus and the cytoplasm. 2015-12-01T11:48:55Z k9 Smad_P_N 
The phosphorylated Smad/Co-Smad complex is shuttled into the nucleus. Annotations are for the SMAD domain and for Smad protein import into the nucleus.
 r19 STATE_TRANSITION Smad protein shuttling between the nucleus and the cytoplasm. 2015-12-01T11:48:54Z Function_for_r16__1 Smad_P_CoSmad k12 k8 
Nuclear Smad is dephosphorylated. Annotations are for the SMAD domain and for protein dephosphorylation.
 r20 STATE_TRANSITION 0.8680694509782816,-0.3464028304982998 Smad dephosphorylation and nuclear export are coupled during TGF-beta signaling. 2015-12-01T11:46:57Z n k13 Smad_P_N 
Phosphorylated nuclear Smads form a dimer. Annotations are for Smad protein complex assembly and for the SMAD domain contained in both Smad proteins.
 r21 STATE_TRANSITION 0.43590557203228064,0.4783149342737669 The formation of Smad transcriptional complexes is affected by mono-ubiquitinated Smad4. 2015-12-01T14:19:44Z n k10 Smad_P_N 2 
Nuclear phosphorylated Smad homodimer dissociated into nuclear phosphorylated Smad monomers.

InterPro annotation gives details on and source information for general Smads (including R-Smad and Co-Smad, as utilized in this reaction). 

Gene Ontology GO:0043241 reference outlines terms associated with protein complex disassembly.

Gene Ontology GO:0010862 reference outlines terms associated with SMAD protein phosphorylation, a critical element of setting up SMAD_P elements.

This reaction occurs in the nucleus.

All annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 r22 STATE_TRANSITION 0.5161712047441155,-0.49275743901746427 2015-12-01T14:19:45Z n k11 Smad_P_Smad_P_N 
Nuclear phosphorylated Smad and Co-Smad heterodimerize.

InterPro annotation gives details on and source information for general Smads (including R-Smad and Co-Smad, as utilized in this reaction). 

GeneOntology GO:0070412 reference outlines terms associated with R-Smad binding, which is the major element associated with this reaction.

Gene Ontology GO:0010862 reference outlines terms associated with SMAD protein phosphorylation, a critical element of setting up SMAD_P elements.

Gene Ontology GO:0070410 references outlines terms associated with Co-Smad binding, a major element in this reaction.

Uniprot Q13485 is a Homo sapien version of Smad4, the Smad indicated as a Co-Smad by the model authors.

This reaction occurs in the nucleus.

Most annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 r23 STATE_TRANSITION 0.9190684664964126,0.2577526450200649 2015-12-01T14:19:46Z n k10 Smad_P_N CoSmad_N 
Nuclear phosphorylated Smad and Co-Smad disocciate into phosphorylated Smad and Co-Smad monomers.

InterPro annotation gives details on and source information for general Smads (including R-Smad and Co-Smad, as utilized in this reaction). 

Gene Ontology GO:0043241 reference outlines terms associated with protein complex disassembly.

Gene Ontology GO:0010862 reference outlines terms associated with SMAD protein phosphorylation, a critical element of setting up SMAD_P elements.

Gene Ontology GO:0070410 references outlines terms associated with Co-Smad binding, a major element in this reaction (though unbinding is focus of reaction).

Uniprot Q13485 is a Homo sapien version of Smad4, the Smad indicated as a Co-Smad by the model authors.

This reaction occurs in nucleus.

All annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.).
 r24 STATE_TRANSITION 0.06925690596867362,-0.23403782810143703 2015-12-01T14:19:51Z n k11 Smad_P_CoSmad_N 
I-Smad mRNA is created in the nucleus, a process which is inhibited by the nuclear phosphorylated Smad and Co-Smad heterodimer.


InterPro annotation gives details on and source information for general Smads (including I-Smads, as encoded for by the product of this reaction). 

This reaction occurs in the nucleus.

All annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 r25 STATE_TRANSITION 2015-12-01T14:19:52Z n Function_for_r25__1 Smad_P_CoSmad_N h k14 k15 
Nuclear I-Smad mRNA is shuttled to the cytoplasm.

InterPro annotation gives details on and source information for general Smads (including I-Smads, as encoded for by the product of this reaction). 

Gene Ontology GO:0006913 gives terms associated with nuclear export; this reaction involves, specifically, nucleus to cytoplasm transport.

All annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 r26 STATE_TRANSITION 2015-12-01T15:48:04Z k16 I_Smad_mRNA1 
Cytoplasmic I-Smad mRNA is degraded.

InterPro annotation gives details on and source information for general Smads (including I-Smads, as encoded for by the reactant of this reaction if not degraded as shown). 

Gene Ontology GO:0006401 gives the terms associated with RNA catabolic processes; this reaction specifically utilizes RNA breakdown/decay/degradation in the cytoplasm.

This reaction occurs in the cytoplasm.

All annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 r27 STATE_TRANSITION 2015-12-01T15:48:21Z c k17 I_Smad_mRNA2 
I-Smad is generated, a process which is limited by cytoplasmi I-Smad mRNA.

InterPro annotation gives details on and source information for general Smads (including I-Smads, which are given rise to in this reaction). 

This reaction occurs in the cytoplasm. 

All annotations are generalized as the model details general TGFb pathway dynamics across relevant species (i.e. Homo sapiens, Drosophila, etc.)
 r28 STATE_TRANSITION 2015-12-01T15:49:37Z c Function_for_r28__1 I_Smad_mRNA2 k18 
Degradation of I-Smad.
 r29 STATE_TRANSITION 2015-12-01T15:52:19Z c k19 I_Smad