PICK1 promotes caveolin-dependent degradation of TGF-β type i receptor

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Abstract

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. © 2012 IBCB, SIBS, CAS All rights reserved.

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Zhao, B., Wang, Q., Du, J., Luo, S., Xia, J., & Chen, Y. G. (2012). PICK1 promotes caveolin-dependent degradation of TGF-β type i receptor. Cell Research, 22(10), 1467–1478. https://doi.org/10.1038/cr.2012.92

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