转化生长因子β（TGF-β）在调节细胞增殖、分化、迁移和死亡中有重要作用。TGF-β的异常与许多病理变化有关，例如血管疾病和癌症。PICK1（Protein that interacts with C kinase 1 ）是含有PDZ和BAR结构域的蛋白，有研究认为，PICK1能够与多种细胞膜表面的受体结合，调节亚细胞水平信号的传递。以往对PICK1的研究表明其与记忆的形成和其它神经系统活动有关，但PICK1在多种组织中表达，如心脏、睾丸、肝、肾。因此它可能还具有除神经功能以外的其他作用。
本文中，研究者发现PICK有拮抗TGF-β信号通路的作用。而这种作用是通过降解TGF-β的1型受体（TGF-β type I receptor ，TβRI）来实现的。实验表明PICK1的PDZ结构域能够直接与TβRI蛋白的C末端结合，并充当鹰架蛋白增强TβRI与小窝蛋白1（caveolin-1）之间的相互作用。因此PICK1促进了小窝蛋白介导的TβRI的内吞和泛素化降解。
此外，在乳腺癌中，PICK1的表达与TβRI和磷酸化的Smad2水平呈负相关。这说明，PICK1有可能通过抑制TGF-β途径参与了乳腺癌的发生。（生物谷 Bioon.com ）
doi:10.1038/cr.2012.92
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PICK1 promotes caveolin-dependent degradation of TGF-β type I receptor
Bing Zhao1, Qiang Wang1,4, Jun Du1, Shiwen Luo2, Jun Xia3 and Ye-Guang Chen
Protein that interacts with C kinase 1 (PICK1) is a critical mediator of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking in neural synapses. However, its ubiquitous expression suggests that it may have other non-neural functions. Here we show that PICK1 antagonizes transforming growth factor beta (TGF-β) signaling by targeting TGF-β type I receptor (TβRI) for degradation. Biochemical analyses reveal that PICK1 directly interacts with the C-terminus of TβRI via its PDZ domain and acts as a scaffold protein to enhance the interaction between TβRI and caveolin-1, leading to enhanced lipid raft/caveolae localization. Therefore, PICK1 increases caveolin-mediated endocytosis, ubiquitination and degradation of TβRI. Moreover, a negative correlation between PICK1 expression and TβRI or phospho-Smad2 levels is observed in human breast tumors, indicating that PICK1 may participate in breast cancer development through inhibition of TGF-β signaling. Our findings reveal a non-neural function of PICK1 as an important negative regulator of TGF-β signaling.
