轉(zhuǎn)化生長因子β（TGF-β）在調(diào)節(jié)細胞增殖,、分化、遷移和死亡中有重要作用,。TGF-β的異常與許多病理變化有關(guān)，例如血管疾病和癌癥,。PICK1（Protein that interacts with C kinase 1 ）是含有PDZ和BAR結(jié)構(gòu)域的蛋白，有研究認為,，PICK1能夠與多種細胞膜表面的受體結(jié)合,，調(diào)節(jié)亞細胞水平信號的傳遞。以往對PICK1的研究表明其與記憶的形成和其它神經(jīng)系統(tǒng)活動有關(guān),，但PICK1在多種組織中表達,，如心臟、睪丸,、肝,、腎,。因此它可能還具有除神經(jīng)功能以外的其他作用。
本文中,，研究者發(fā)現(xiàn)PICK有拮抗TGF-β信號通路的作用,。而這種作用是通過降解TGF-β的1型受體（TGF-β type I receptor ,，TβRI）來實現(xiàn)的,。實驗表明PICK1的PDZ結(jié)構(gòu)域能夠直接與TβRI蛋白的C末端結(jié)合,，并充當鷹架蛋白增強TβRI與小窩蛋白1（caveolin-1）之間的相互作用,。因此PICK1促進了小窩蛋白介導(dǎo)的TβRI的內(nèi)吞和泛素化降解。
此外,，在乳腺癌中,，PICK1的表達與TβRI和磷酸化的Smad2水平呈負相關(guān)。這說明,，PICK1有可能通過抑制TGF-β途徑參與了乳腺癌的發(fā)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.
