Nephrocystin interacts with Pyk2, p130(Cas), and tensin and triggers phosphorylation of Pyk2

Juvenile nephronophthisis type 1 is caused by mutations of NPHP1, the gene encoding for nephrocystin. The function of nephrocystin is presently unknow n, but the presence of a Src homology 3 domain and its recently described i nteraction with p130(Cas) suggest that nephrocystin is part of the focal ad hesion signaling complex. We generated a nephrocystin-specific antiserum an d analyzed the interaction of native nephrocystin with endogenous proteins. Immunoprecipitation of nephrocystin revealed that nephrocystin forms prote in complexes with p130(Cas), proline-rich tyrosine kinase 2 (Pyk2), and ten sin, indicating that these proteins participate in a common signaling pathw ay. Expression of nephrocystin resulted in phosphorylation of Pyk2 on tyros ine 402 as well as activation of downstream mitogen-activated protein kinas es, such as ERK1 and ERK2. Our findings suggest that nephrocystin helps to recruit Pyk2 to cell matrix adhesions, thereby initiating phosphorylation o f Pyk2 and Pyk2-dependent signaling. A lack of functional nephrocystin may compromise Pyk2 signaling in a subset of renal epithelial cells.