α- and γ-protocadherins negatively regulate PYK2

Genetic studies demonstrate that γ-protocadherins (PCDH-γ) are required for the survival and synaptic connectivity in neuronal subpopulations of the central nervous system. However, the intracellular signaling mechanisms for PCDH-γ are poorly understood. Here, we show that PCDH-γ binds two tyrosine kinases, PYK2 and focal adhesion kinase (FAK), and interaction with PCDH-γ inhibits kinase activity. Consistent with this, PYK2 activity is abnormally up-regulated in the Pcdh-γ-deficient neurons. Overexpression of PYK2 induces apoptosis in the chicken spinal cord. Thus, negative regulation of PYK2 activity by PCDH could contribute to the survival of subsets of neurons. Surprisingly, we found that PCDH-α interacts similarly with PYK2 and FAK despite containing a distinct cytoplasmic domain. In neural tissue, PCDH-γ, together with PCDH-α, forms functional complexes with PYK2 and/or FAK. Therefore, the identification of common intracellular effectors for PCDH-γ and PCDH-α suggests that dozens of protocadherins generated by Pcdh-α and Pcdh-γ gene clusters can converge different extracellular signals into common intracellular pathways.