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PDZK1-interacting protein 1 (PDZK1IP1) traps Smad4 protein and suppresses transforming growth factor-β (TGF-β) signaling.

Authors :
Ikeno S
Nakano N
Sano K
Minowa T
Sato W
Akatsu R
Sakata N
Hanagata N
Fujii M
Itoh F
Itoh S
Source :
The Journal of biological chemistry [J Biol Chem] 2019 Mar 29; Vol. 294 (13), pp. 4966-4980. Date of Electronic Publication: 2019 Feb 04.
Publication Year :
2019

Abstract

Transforming growth factor (TGF)-β signaling in humans is stringently regulated to prevent excessive TGF-β signaling. In tumors, TGF-β signaling can both negatively and positively regulate tumorigenesis dependent on tumor type, but the reason for these opposite effects is unclear. TGF-β signaling is mainly mediated via the Smad-dependent pathway, and herein we found that PDZK1-interacting protein 1 (PDZK1IP1) interacts with Smad4. PDZK1IP1 inhibited both the TGF-β and the bone morphogenetic protein (BMP) pathways without affecting receptor-regulated Smad (R-Smad) phosphorylation. Rather than targeting R-Smad phosphorylation, PDZK1IP1 could interfere with TGF-β- and BMP-induced R-Smad/Smad4 complex formation. Of note, PDZK1IP1 retained Smad4 in the cytoplasm of TGF-β-stimulated cells. To pinpoint PDZK1IP1's functional domain, we created several PDZK1IP1 variants and found that its middle region, from Phe <superscript>40</superscript> to Ala <superscript>49</superscript> , plays a key role in its Smad4-regulating activity. PDZK1IP1 knockdown enhanced the expression of the TGF-β target genes Smad7 and prostate transmembrane protein androgen-induced (TMEPAI) upon TGF-β stimulation. In contrast, PDZK1IP1 overexpression suppressed TGF-β-induced reporter activities, cell migration, and cell growth inhibition. In a xenograft tumor model in which TGF-β was previously shown to elicit tumor-promoting effects, PDZK1IP1 gain of function decreased tumor size and increased survival rates. Taken together, these findings indicate that PDZK1IP1 interacts with Smad4 and thereby suppresses the TGF-β signaling pathway.<br /> (© 2019 Ikeno et al.)

Details

Language :
English
ISSN :
1083-351X
Volume :
294
Issue :
13
Database :
MEDLINE
Journal :
The Journal of biological chemistry
Publication Type :
Academic Journal
Accession number :
30718277
Full Text :
https://doi.org/10.1074/jbc.RA118.004153