Nephrocystin-4 Regulates Pyk2-induced Tyrosine Phosphorylation of Nephrocystin-1 to Control Targeting to Monocilia

ArticleinJournal of Biological Chemistry 286(16):14237-45 · February 2011with23 Reads
Impact Factor: 4.57 · DOI: 10.1074/jbc.M110.165464 · Source: PubMed

    Abstract

    Nephronophthisis is the most common genetic cause of end-stage renal failure during childhood and adolescence. Genetic studies
    have identified disease-causing mutations in at least 11 different genes (NPHP1–11), but the function of the corresponding nephrocystin proteins remains poorly understood. The two evolutionarily conserved
    proteins nephrocystin-1 (NPHP1) and nephrocystin-4 (NPHP4) interact and localize to cilia in kidney, retina, and brain characterizing
    nephronophthisis and associated pathologies as result of a ciliopathy. Here we show that NPHP4, but not truncating patient
    mutations, negatively regulates tyrosine phosphorylation of NPHP1. NPHP4 counteracts Pyk2-mediated phosphorylation of three
    defined tyrosine residues of NPHP1 thereby controlling binding of NPHP1 to the trans-Golgi sorting protein PACS-1. Knockdown
    of NPHP4 resulted in an accumulation of NPHP1 in trans-Golgi vesicles of ciliated retinal epithelial cells. These data strongly
    suggest that NPHP4 acts upstream of NPHP1 in a common pathway and support the concept of a role for nephrocystin proteins
    in intracellular vesicular transport.