CNKSR2 scaffold function in the mammalian nervous system

CNKSR proteins are multidomain scaffold proteins that coordinate protein complex formation and regulate intracellular signaling via diverse protein-protein interactions. Here, we focus on CNKSR2 (also known as CNK2 or MAGUIN), which is encoded by one of three vertebrate CNKSR genes that have undergone diversification and specification over the course of evolution, since the emergence of the earliest CNKSR-like modular proteins, which are observed already in the genome sequences of Porifera (sponges). The vertebrate CNKSR2 protein is unique in that it is the only CNKSR scaffold molecule with substantial expression in the central nervous system, and also the only CNKSR scaffold molecule for which there is a clear causal link to disease; patients with mutations that affect the function of the CNKSR2 protein suffer from a neurodevelopmental seizure disorder. For this reason in particular, understanding the cellular signalling cascades that are regulated by the CNKSR2 protein are of essential importance. In this review, we introduce the CNKSR proteins with their evolutionary trajectory, followed by an overview of available data on the vertebrate CNKSR2, with the aim to provide a concise summary of what is known about the expression and function of CNKSR2 in neurons of the central nervous system.