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

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.

Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-β Signaling Pathway

“…38 Furthermore, PICK1 was recently reported to increase caveolin-dependent endocytosis of TβRI, which promotes its degradation, and its effect was abolished by inhibition of autophagy. 27 Here, we uncovered a direct interaction between Sirt7 and PICK1, and we demonstrated that PICK1 knockdown rescues the effect of Sirt7 depletion on the reduction of TβRI. In Figure 7E and 7G, PICK1 was decreased by autophagy activator or Sirt7 siRNA, but it was increased by autophagy inhibitor.…”

“…We focused on protein interacting with protein kinase-Cα (PICK1) because it has been shown to interact with TβRI and to increase TβRI degradation, and its effect was abolished by inhibition of autophagy. 27 In cardiac fibroblasts, the PICK1 protein level decreased by Sirt7 knockdown and by autophagy activator, whereas its level increased by autophagy inhibitor (Figure 7E and 7G). These results indicate that the PICK1 level changes in parallel with TβRI, depending on the status of autophagy.…”

PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway

“…43 Very recently it was shown that PICK, a critical mediator of AMPAR trafficking in neuronal synapses, is overexpressed in breast cancer and antagonizes TGF-β1 signaling by promoting caveolin-dependent degradation of TβRI, thus abolishing TGF-β1-induced growth inhibition. 44,45 However, it was also reported that TβRI is a target of homeoprotein Six1 and Six1-induced upregulation of TβRI is required to switch of TGF-βI signaling to the prometastatic phenotype, such as EMT. 46 Although our study reveals that modulation of either TβRI or TβRII by PPARδ-ABCA1-Cav1 signaling provokes similar effect in prostate carcinoma cells, further studies are required to clarify whether TβRI and TβRII have differential functions in the shift of TGF-βI signaling depending on cellular context and origins.…”

Internalization of the TGF-β type I receptor into caveolin-1 and EEA1 double-positive early endosomes

“…Caveolae-mediated endocytosis has been shown to negatively regulate TGF-β signaling by promoting TGF-β receptor turnover, probably via Smad7/Smurf-catalyzed ubiquitination [8,39]. The existence of caveolin-1 in early endosomes led us to ask whether caveolin-1-positive early endosomes participate in TβRI degradation.…”