PICK1Attenuates TGF-β By Promoting Its Type Ⅰ Receptor Degradation

Transformation growth factor-beta (TGF-β) belongs to a superfamily of structuralrelated cytokines, consisting of TGF-β, Activin, Nodal, BMPs (bone morphogenicproteins), myostatin and others. TGF-β plays critical roles in early embryonicdevelopment and tissue homeostasis. The signal transduction is initiated via the ligandbinding to two cell surface receptors (type I and type II receptors), and then the Ser/Thrkinase in the intracellular domain of the type I receptor phosphorylates the signalingmediators Smad proteins, leading to their nuclear accumulation and their regulation oftarget gene expression. TGF-β signaling is precisely controlled spatiotemporally, and itsderegulation has been associated with development of human diseases including cancerand tissue fibrosis.PICK1(Protein that interacts with C kinase1) has been well studied in neuralsystem. Its classic function is controlling the endocytosis and trafficking ofα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in neuralsynapses. PICK1has ubiquitous expression in many organs including heart, lung, liverand kidney. The non-neural functions of PICK1are less addressed, and its potentialeffects on signal transduction and related diseases remain unclear.Here we find that overexpression of PICK1inhibits TGF-β signaling transductionin various cell lines. Knockout of Pick1efficiently prolongs the halflife of TGF-β type Ireceptor (TβRI) and promotes the response of mouse embryonic fibroblast to TGF-βtreatment. Biochemical analyses reveal that PICK1antagonizes TGF-β signaling bytargeting TGF-β type I receptor (TβRI) for proteasome-mediated andlysosome-mediated degradation. PICK1can directly interact with the C-terminus ofTβRI via its PDZ domain and act as a scaffold protein to promote the interactionbetween TβRI and caveolin-1, leading to enhanced lipid raft/caveolae localization ofTβRI. Therefore, PICK1increases caveolin-1-mediated endocytosis, ubiquitination anddegradation of TβRI. Finally, a negative correlation between PICK1expression andTβRI or phospho-Smad2levels is observed in human breast tumors, indicating thatPICK1may participate in breast cancer development through inhibition of TGF-βsignaling. Our findings reveal a novel function of PICK1as an important negativeregulator of TGF-β signaling. Not only does this study reveal the relationship between PICK1and TGF-β signal transduction, but also it provides new insight intophysiological and pathological functions of PICK1, especially its effects on tumordevelopment.