Schalm, Stefanie S.Ballif, Bryan A.Buchanan, SeanPhillips, Greg R.Maniatis, Thomas2023-05-222010Schalm, S. S., B. A. Ballif, S. M. Buchanan, G. R. Phillips, and T. Maniatis. 2010. “Phosphorylation of Protocadherin Proteins by the Receptor Tyrosine Kinase Ret.” Proceedings of the National Academy of Sciences 107 (31) (June 25): 13894–13899.0027-8424https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37375302The 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.en-USintracellular domainsignal transductionTAP tagprotein-protein interactionsprotein purificationJournal Article2023-05-2210.1073/pnas.1007182107