III 型 TGF-β 受体通过 GIPC 介导的 TGF-β 信号抑制抑制乳腺癌的进展。
The type III TGF-beta receptor suppresses breast cancer progression through GIPC-mediated inhibition of TGF-beta signaling.
机构信息
Department of Medicine, Duke University Medical Center, Durham, NC 27708, USA.
出版信息
Carcinogenesis. 2010 Feb;31(2):175-83. doi: 10.1093/carcin/bgp271. Epub 2009 Dec 2.
Abstract
Loss of expression of the type III transforming growth factor-beta receptor (TbetaRIII or betaglycan), a transforming growth factor-beta (TGF-beta) superfamily co-receptor, is common in human breast cancers. TbetaRIII suppresses cancer progression in vivo by reducing cancer cell migration and invasion by largely unknown mechanisms. Here, we demonstrate that the cytoplasmic domain of TbetaRIII is essential for TbetaRIII-mediated downregulation of migration and invasion in vitro and TbetaRIII-mediated inhibition of breast cancer progression in vivo. Functionally, the cytoplasmic domain of TbetaRIII is required to attenuate TGF-beta signaling, whereas TbetaRIII-mediated attenuation of TGF-beta signaling is required for TbetaRIII-mediated inhibition of migration and invasion. Mechanistically, both TbetaRIII-mediated inhibition of TGF-beta signaling and TbetaRIII-mediated inhibition of invasion occur through the interaction of the cytoplasmic domain of TbetaRIII with the scaffolding protein GAIP-interacting protein C-terminus (GIPC). Taken together, these studies support a functional role for the TbetaRIII cytoplasmic domain interacting with GIPC to suppress breast cancer progression.
摘要
III 型转化生长因子-β 受体（TβRIII 或β糖蛋白）的表达缺失是人类乳腺癌中的常见现象。TβRIII 作为转化生长因子-β（TGF-β）超家族的共受体，通过降低癌细胞的迁移和侵袭，在体内抑制癌症的进展，但其中的机制尚不清楚。本研究证明，TβRIII 的细胞质结构域对于 TβRIII 介导的体外迁移和侵袭下调以及 TβRIII 介导的体内乳腺癌进展抑制是必需的。功能上，TβRIII 的细胞质结构域需要减弱 TGF-β 信号，而 TβRIII 介导的 TGF-β 信号减弱对于 TβRIII 介导的迁移和侵袭抑制是必需的。从机制上讲，TβRIII 抑制 TGF-β 信号和 TβRIII 抑制侵袭都需要 TβRIII 细胞质结构域与支架蛋白 GAIP 相互作用蛋白 C 末端（GIPC）相互作用。综上所述，这些研究支持 TβRIII 细胞质结构域与 GIPC 相互作用以抑制乳腺癌进展的功能作用。
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