The BAR Domain Protein PICK1 Regulates Cell Recognition and Morphogenesis by Interacting with Neph Proteins

Abstract

ABSTRACTNeph proteins are evolutionarily conserved membrane proteins of the immunoglobulin superfamily that control the formation of specific intercellular contacts. Cell recognition through these proteins is essential in diverse cellular contexts such as patterning of the compound eye inDrosophila melanogaster, neuronal connectivity inCaenorhabditis elegans, and the formation of the kidney filtration barrier in mammals. Here we identify the PDZ and BAR domain protein PICK1 (protein interacting with C-kinase 1) as a Neph-interacting protein. Binding required dimerization of PICK1, was dependent on PDZ domain protein interactions, and mediated stabilization of Neph1 at the plasma membrane. Moreover, protein kinase C (PKCα) activity facilitated the interaction through releasing Neph proteins from their binding to the multidomain scaffolding protein zonula occludens 1 (ZO-1), another PDZ domain protein. InDrosophila, the Neph homologue Roughest is essential for sorting of interommatidial precursor cells and patterning of the compound eye. RNA interference-mediated knockdown of PICK1 in theDrosophilaeye imaginal disc caused a Roughest destabilization at the plasma membrane and a phenotype that resembledrstmutation. These data indicate that Neph proteins and PICK1 synergistically regulate cell recognition and contact formation.