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2015 ; 13
(12
): e1002325
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ShcA Protects against Epithelial-Mesenchymal Transition through Compartmentalized
Inhibition of TGF-?-Induced Smad Activation
#MMPMID26680585
Muthusamy BP
; Budi EH
; Katsuno Y
; Lee MK
; Smith SM
; Mirza AM
; Akhurst RJ
; Derynck R
PLoS Biol
2015[Dec]; 13
(12
): e1002325
PMID26680585
show ga
Epithelial-mesenchymal transition (EMT) is a normal cell differentiation event
during development and contributes pathologically to carcinoma and fibrosis
progression. EMT often associates with increased transforming growth factor-?
(TGF-?) signaling, and TGF-? drives EMT, in part through Smad-mediated
reprogramming of gene expression. TGF-? also activates the Erk MAPK pathway
through recruitment and Tyr phosphorylation of the adaptor protein ShcA by the
activated TGF-? type I receptor. We found that ShcA protects the epithelial
integrity of nontransformed cells against EMT by repressing TGF-?-induced,
Smad-mediated gene expression. p52ShcA competed with Smad3 for TGF-? receptor
binding, and down-regulation of ShcA expression enhanced autocrine TGF-?/Smad
signaling and target gene expression, whereas increased p52ShcA expression
resulted in decreased Smad3 binding to the TGF-? receptor, decreased Smad3
activation, and increased Erk MAPK and Akt signaling. Furthermore, p52ShcA
sequestered TGF-? receptor complexes to caveolin-associated membrane
compartments, and reducing ShcA expression enhanced the receptor localization in
clathrin-associated membrane compartments that enable Smad activation.
Consequently, silencing ShcA expression induced EMT, with increased cell
migration, invasion, and dissemination, and increased stem cell generation and
mammosphere formation, dependent upon autocrine TGF-? signaling. These findings
position ShcA as a determinant of the epithelial phenotype by repressing
TGF-?-induced Smad activation through differential partitioning of receptor
complexes at the cell surface.