PICK1 promotes caveolin-dependent degradation of TGF-beta type I receptor

Protein that interacts with C kinase 1 (PICK1) is a critical mediator of alpha-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-beta) signaling by targeting TGF-beta type I receptor (T beta RI) for degradation. Biochemical analyses reveal that PICK1 directly interacts with the C-terminus of T beta RI via its PDZ domain and acts as a scaffold protein to enhance the interaction between T beta RI and caveolin-1, leading to enhanced lipid raft/caveolae localization. Therefore, PICK1 increases caveolin-mediated endocytosis, ubiquitination and degradation of T beta RI. Moreover, a negative correlation between PICK1 expression and T beta RI or phospho-Smad2 levels is observed in human breast tumors, indicating that PICK1 may participate in breast cancer development through inhibition of TGF-beta signaling. Our findings reveal a non-neural function of PICK1 as an important negative regulator of TGF-beta signaling.