期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 31, 页码 13894-13899出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1007182107
关键词
intracellular domain; signal transduction; TAP tag; protein-protein interactions; protein purification
资金
- National Institutes of Health [R01NS043915]
- Vermont Genetics Network through National Institutes of Health [P20 RR16462]
- IDeA Networks of Biomedical Research Excellence (INBRE) of the National Center for Research Resources (NCRR)
- Irma T. Hirschl Research Award
- [NS051238]
The clustered protocadherins (Pcdhs) are a large family of cadherin-like transmembrane proteins expressed in the nervous system. Stochastic expression of Pcdh genes and alternative splicing of their pre-mRNAs have the potential to generate enormous protein diversity at the cell surface of neurons. At present, the regulation and function of Pcdh proteins are largely unknown. Here, we show that Pcdhs form a heteromeric signaling complex(es), consisting of multiple Pcdh isoforms, receptor tyrosine kinases, phosphatases, and cell adhesion molecules. In particular, we find that the receptor tyrosine kinase rearranged during transformation (Ret) binds to Pcdhs in differentiated neuroblastoma cells and is required for stabilization and differentiation-induced phosphorylation of Pcdh proteins. In addition, the Ret ligand glial cell line-derived neurotrophic factor induces phosphorylation of Pcdh gamma in motor neurons and phosphorylation of Pcdh alpha and Pcdh gamma in sympathetic neurons. Conversely, Pcdh proteins are also required for the stabilization of activated Ret in neuroblastoma cells and sympathetic ganglia. Thus, Pcdhs and Ret are functional components of a phosphorylation-dependent signaling complex.
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