NDLI: Phosphorylation of Nephrin Triggers Ca2+ Signaling by Recruitment and Activation of Phospholipase C-γ1*

Content Provider	PubMed Central
Author	Harita, Yutaka Kurihara, Hidetake Kosako, Hidetaka Tezuka, Tohru Sekine, Takashi Igarashi, Takashi Ohsawa, Ikuroh Ohta, Shigeo Hattori, Seisuke
Abstract	A specialized intercellular junction between podocytes, known as the slit diaphragm (SD), forms the essential structural frame-work for glomerular filtration in the kidney. In addition, mounting evidence demonstrates that the SD also plays a crucial role as a signaling platform in physiological and pathological states. Nephrin, the major component of the SD, is tyrosine-phosphorylated by a Src family tyrosine kinase, Fyn, in developing or injured podocytes, recruiting Nck to Nephrin via its Src homology 2 domain to regulate dynamic actin remodeling. Dysregulated Ca2+ homeostasis has also been implicated in podocyte damage, but the mechanism of how podocytes respond to injury is largely unknown. Here we have identified phospholipase C-γ1 (PLC-γ1) as a novel phospho-Nephrin-binding protein. When HEK293T cells expressing a chimeric protein consisting of CD8 and Nephrin cytoplasmic domain (CD) were treated with anti-CD8 and anti-mouse antibodies, clustering of Nephrin and phosphorylation of Nephrin-CD were induced. Upon this clustering, PLC-γ1 was bound to phosphorylated Nephrin Tyr-1204, which induced translocation of PLC-γ1 from cytoplasm to the CD8/Nephrin cluster on the plasma membrane. The recruitment of PLC-γ1 to Nephrin activated PLC-γ1, as detected by phosphorylation of PLC-γ1 Tyr-783 and increase in inositol 1,4,5-trisphosphate level. We also found that Nephrin Tyr-1204 phosphorylation triggers the Ca2+ response in a PLC-γ1-dependent fashion. Furthermore, PLC-γ1 is significantly phosphorylated in injured podocytes in vivo. Given the profound effect of PLC-γ in diverse cellular functions, regulation of the Ca2+ signaling by Nephrin may be important in modulating the glomerular filtration barrier function.
Related Links	http://dx.doi.org/10.1074/jbc.m806851200
Ending Page	8962
Page Count	12
Starting Page	8951
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	13
Volume Number	284
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2009-03-27
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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