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

ABSTRACT: Transforming growth factor (TGF)-? signaling in humans is stringently regulated to prevent excessive TGF-? signaling. In tumors, TGF-? signaling can both negatively and positively regulate tumorigenesis dependent on tumor type, but the reason for these opposite effects is unclear. TGF-? 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-? 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-?- and BMP-induced R-Smad/Smad4 complex formation. Of note, PDZK1IP1 retained Smad4 in the cytoplasm of TGF-?-stimulated cells. To pinpoint PDZK1IP1's functional domain, we created several PDZK1IP1 variants and found that its middle region, from Phe40 to Ala49, plays a key role in its Smad4-regulating activity. PDZK1IP1 knockdown enhanced the expression of the TGF-? target genes Smad7 and prostate transmembrane protein androgen-induced (TMEPAI) upon TGF-? stimulation. In contrast, PDZK1IP1 overexpression suppressed TGF-?-induced reporter activities, cell migration, and cell growth inhibition. In a xenograft tumor model in which TGF-? 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-? signaling pathway.

SUBMITTER: Ikeno S 

PROVIDER: S-EPMC6442039 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature