PICK1 promotes caveolin-dependent degradation of TGF-β typel receptor

Protein that interacts with C kinase 1 （PICK1） is a critical mediator of a-amino-3-hydroxy-5-methyl-4-isoxazole- propionic 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 TIiRI 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-Iβ signaling. Our findings reveal a non-neural function of PICK1 as an important negative regulator of TGF-Iβ signaling.