PDZK1-interacting protein 1 (PDZK1IP1) traps Smad4 protein and suppresses transforming growth factor-β (TGF-β) signaling
PDZK1-interacting protein 1 (PDZK1IP1) traps Smad4 protein and suppresses transforming growth factor-β (TGF-β) signaling
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DOI：
10.1074/jbc.ra118.004153
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发表时间：
2019-03-29
影响因子：
4.8
通讯作者：
Itoh, Susumu
中科院分区：
文献类型：
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作者：
Ikeno, Souichi;Nakano, Naoko;Itoh, Susumu
人类转化生长因子 (TGF)-β 信号传导受到严格监管，以防止过度的 TGF-β 信号传导。在肿瘤中，TGF-β信号传导可以根据肿瘤类型对肿瘤发生进行负向和正向调节，但产生这些相反作用的原因尚不清楚。 TGF-β信号传导主要通过Smad依赖性途径介导，在此我们发现PDZK1相互作用蛋白1（PDZK1IP1）与Smad4相互作用。 PDZK1IP1 抑制 TGF-β 和骨形态发生蛋白 (BMP) 通路，而不影响受体调节的 Smad (R-Smad) 磷酸化。 PDZK1IP1 不是针对 R-Smad 磷酸化，而是干扰 TGF-β 和 BMP 诱导的 R-Smad/Smad4 复合物形成。值得注意的是，PDZK1IP1 在 TGF-β 刺激的细胞的细胞质中保留了 Smad4。为了查明 PDZK1IP1 的功能域，我们创建了几个 PDZK1IP1 变体，并发现其中间区域，从 Phe(40) 到 Ala(49)，在其 Smad4 调节活性中发挥着关键作用。 PDZK1IP1 敲除增强了 TGF-β 刺激后 TGF-β 靶基因 Smad7 和前列腺跨膜蛋白雄激素诱导 (TMEPAI) 的表达。相反，PDZK1IP1 过表达抑制 TGF-β 诱导的报告基因活性、细胞迁移和细胞生长抑制。在异种移植肿瘤模型中，TGF-β 先前已被证明可引发肿瘤促进作用，PDZK1IP1 功能的获得可减小肿瘤大小并提高存活率。综上所述，这些发现表明 PDZK1IP1 与 Smad4 相互作用，从而抑制 TGF-β 信号通路。
Transforming growth factor (TGF)-beta signaling in humans is stringently regulated to prevent excessive TGF-beta signaling. In tumors, TGF-beta signaling can both negatively and positively regulate tumorigenesis dependent on tumor type, but the reason for these opposite effects is unclear. TGF-beta 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-beta 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-beta- and BMP-induced R-Smad/Smad4 complex formation. Of note, PDZK1IP1 retained Smad4 in the cytoplasm of TGF-beta-stimulated cells. To pinpoint PDZK1IP1's functional domain, we created several PDZK1IP1 variants and found that its middle region, from Phe(40) to Ala(49), plays a key role in its Smad4-regulating activity. PDZK1IP1 knockdown enhanced the expression of the TGF-beta target genes Smad7 and prostate transmembrane protein androgen-induced (TMEPAI) upon TGF-beta stimulation. In contrast, PDZK1IP1 overexpression suppressed TGF-beta-induced reporter activities, cell migration, and cell growth inhibition. In a xenograft tumor model in which TGF-beta 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-beta signaling pathway.