Referenced in: none

Automatically associated channels: Kv1.3 , Kv1.5

Title: Sequestosome1/p62: a regulator of redox-sensitive voltage-activated potassium channels, arterial remodeling, inflammation, and neurite outgrowth.

Authors: Tetsuro Ishii, Eiji Warabi, Richard C M Siow, Giovanni E Mann

Journal, date & volume: Free Radic. Biol. Med., 2013 Dec , 65, 102-16

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23792273

Abstract
Sequestosome1/p62 (SQSTM1) is an oxidative stress-inducible protein regulated by the redox-sensitive transcription factor Nrf2. It is not an antioxidant but known as a multifunctional regulator of cell signaling with an ability to modulate targeted or selective degradation of proteins through autophagy. SQSTM1 implements these functions through physical interactions with different types of proteins including atypical PKCs, nonreceptor-type tyrosine kinase p56(Lck) (Lck), polyubiquitin, and autophagosomal factor LC3. One of the notable physiological functions of SQSTM1 is the regulation of redox-sensitive voltage-gated potassium (Kv) channels which are composed of α and β subunits: (Kvα)4 (Kvβ)4. Previous studies have established that SQSTM1 scaffolds PKCζ, enhancing phosphorylation of Kvβ which induces inhibition of pulmonary arterial Kv1.5 channels under acute hypoxia. Recent studies reveal that Lck indirectly interacts with Kv1.3 α subunits and plays a key role in acute hypoxia-induced Kv1.3 channel inhibition in T lymphocytes. Kv1.3 channels provide a signaling platform to modulate the migration and proliferation of arterial smooth muscle cells and activation of T lymphocytes, and hence have been recognized as a therapeutic target for treatment of restenosis and autoimmune diseases. In this review, we focus on the functional interactions of SQSTM1 with Kv channels through two key partners aPKCs and Lck. Furthermore, we provide molecular insights into the functions of SQSTM1 in suppression of proliferation of arterial smooth muscle cells and neointimal hyperplasia following carotid artery ligation, in T lymphocyte differentiation and activation, and in NGF-induced neurite outgrowth in PC12 cells.