Abstract
The type II epithelial-mesenchymal transition (EMT) produces airway fibrosis and remodeling, contributing to the severity of asthma and chronic obstructive pulmonary disease. While numerous studies have been done on the mechanisms of the transition itself, few studies have investigated the system effects of EMT on signaling networks. Here, we use mixed effects modeling to develop a computational model of phospho-protein signaling data that compares human small airway epithelial cells (hSAECs) with their EMT-transformed counterparts across a series of perturbations with 8 ligands and 5 inhibitors, revealing previously uncharacterized changes in signaling in the EMT state. Strong couplings between menadione, TNFα and TGFβ and their known phospho-substrates were revealed after mixedeffects modeling. Interestingly, the overall phospho-protein response was attenuated in EMT, with loss of Mena and TNFα coupling to heat shock protein (HSP)-27. These differences persisted after correction for EMT-induced changes in phospho-protein substrate abundance. Construction of network topology maps showed significant changes between the two cellular states, including a linkage between glycogen synthase kinase (GSK)-3α and small body size/mothers against decapentaplegic (SMAD)2. The model also predicted a loss of p38 mitogen activated protein kinase (p38MAPK)-independent HSP27 signaling, which we experimentally validated. We further characterized the relationship between HSP27 and signal transducers and activators of transcription (STAT)3 signaling, and determined that loss of HSP27 following EMT is only partially responsible for the downregulation of STAT3. These rewired connections represent therapeutic targets that could potentially reverse EMT and restore a normal phenotype to the respiratory mucosa.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1413-1425 |
| Number of pages | 13 |
| Journal | Cellular Signalling |
| Volume | 27 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2015 |
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Keywords
- Cellular signaling
- Correlative networks
- EMT
- Mixed-effects modeling
ASJC Scopus subject areas
- Cell Biology
Cite this
Mixed-effects model of epithelial-mesenchymal transition reveals rewiring of signaling networks. / Desai, Poonam; Yang, Jun; Tian, Bing; Sun, Hong; Kalita, Mridul; Ju, Hyunsu; Paulucci-Holthauzen, Adriana; Zhao, Yingxin; Brasier, Allan R.; Sadygov, Rovshan.
In: Cellular Signalling, Vol. 27, No. 7, 01.07.2015, p. 1413-1425.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mixed-effects model of epithelial-mesenchymal transition reveals rewiring of signaling networks
AU - Desai, Poonam
AU - Yang, Jun
AU - Tian, Bing
AU - Sun, Hong
AU - Kalita, Mridul
AU - Ju, Hyunsu
AU - Paulucci-Holthauzen, Adriana
AU - Zhao, Yingxin
AU - Brasier, Allan R.
AU - Sadygov, Rovshan
PY - 2015/7/1
Y1 - 2015/7/1
N2 - The type II epithelial-mesenchymal transition (EMT) produces airway fibrosis and remodeling, contributing to the severity of asthma and chronic obstructive pulmonary disease. While numerous studies have been done on the mechanisms of the transition itself, few studies have investigated the system effects of EMT on signaling networks. Here, we use mixed effects modeling to develop a computational model of phospho-protein signaling data that compares human small airway epithelial cells (hSAECs) with their EMT-transformed counterparts across a series of perturbations with 8 ligands and 5 inhibitors, revealing previously uncharacterized changes in signaling in the EMT state. Strong couplings between menadione, TNFα and TGFβ and their known phospho-substrates were revealed after mixedeffects modeling. Interestingly, the overall phospho-protein response was attenuated in EMT, with loss of Mena and TNFα coupling to heat shock protein (HSP)-27. These differences persisted after correction for EMT-induced changes in phospho-protein substrate abundance. Construction of network topology maps showed significant changes between the two cellular states, including a linkage between glycogen synthase kinase (GSK)-3α and small body size/mothers against decapentaplegic (SMAD)2. The model also predicted a loss of p38 mitogen activated protein kinase (p38MAPK)-independent HSP27 signaling, which we experimentally validated. We further characterized the relationship between HSP27 and signal transducers and activators of transcription (STAT)3 signaling, and determined that loss of HSP27 following EMT is only partially responsible for the downregulation of STAT3. These rewired connections represent therapeutic targets that could potentially reverse EMT and restore a normal phenotype to the respiratory mucosa.
AB - The type II epithelial-mesenchymal transition (EMT) produces airway fibrosis and remodeling, contributing to the severity of asthma and chronic obstructive pulmonary disease. While numerous studies have been done on the mechanisms of the transition itself, few studies have investigated the system effects of EMT on signaling networks. Here, we use mixed effects modeling to develop a computational model of phospho-protein signaling data that compares human small airway epithelial cells (hSAECs) with their EMT-transformed counterparts across a series of perturbations with 8 ligands and 5 inhibitors, revealing previously uncharacterized changes in signaling in the EMT state. Strong couplings between menadione, TNFα and TGFβ and their known phospho-substrates were revealed after mixedeffects modeling. Interestingly, the overall phospho-protein response was attenuated in EMT, with loss of Mena and TNFα coupling to heat shock protein (HSP)-27. These differences persisted after correction for EMT-induced changes in phospho-protein substrate abundance. Construction of network topology maps showed significant changes between the two cellular states, including a linkage between glycogen synthase kinase (GSK)-3α and small body size/mothers against decapentaplegic (SMAD)2. The model also predicted a loss of p38 mitogen activated protein kinase (p38MAPK)-independent HSP27 signaling, which we experimentally validated. We further characterized the relationship between HSP27 and signal transducers and activators of transcription (STAT)3 signaling, and determined that loss of HSP27 following EMT is only partially responsible for the downregulation of STAT3. These rewired connections represent therapeutic targets that could potentially reverse EMT and restore a normal phenotype to the respiratory mucosa.
KW - Cellular signaling
KW - Correlative networks
KW - EMT
KW - Mixed-effects modeling
UR - http://www.scopus.com/inward/record.url?scp=84927725580&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84927725580&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2015.03.024
DO - 10.1016/j.cellsig.2015.03.024
M3 - Article
VL - 27
SP - 1413
EP - 1425
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
IS - 7
ER -