Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 31; pp. 13894 - 13899
• Main Authors: Schalm, Stefanie S., Ballif, Bryan A., Buchanan, Sean M., Phillips, Greg R., Maniatis, Tom
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.08.2010; National Acad Sciences
• Series: From the Cover
• Subjects: Alternative splicing; Animals; Antibodies; Biological Sciences; Cadherins - metabolism; Cell adhesion molecules; Cell Differentiation; Cell lines; Cell surface; Cells; Cells, Cultured; Chromatography, Affinity; Enzyme Activation; Enzyme Stability; Gene expression; Glial cell line-derived neurotrophic factor; Membrane proteins; Mice; Motor neurons; Nervous system; Neuroblastoma cells; Neuroglia; Neurons; Phosphatases; Phosphorylation; Physiological regulation; Protein Binding; Protein isoforms; Protein-tyrosine kinase receptors; Proteins; Proto-Oncogene Proteins c-ret - genetics; Proto-Oncogene Proteins c-ret - metabolism; protocadherin; Receptors; Ret protein; Ribonucleic acid; RNA; Signal Transduction; Stochasticity; Sympathetic ganglia; sympathetic nerves; Transformation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1007182107

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 Pcdhγ in motor neurons and phosphorylation of Pcdhα and Pcdhγ 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.