PICK1 promotes caveolin-dependent degradation of TGF-? type I receptor.

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

SUBMITTER: Zhao B 

PROVIDER: S-EPMC3463259 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature