NYAP: a phosphoprotein family that links PI3K to WAVE1 signalling in neurons

Abstract

The phosphoinositide 3-kinase (PI3K) pathway has been extensively studied in neuronal function and morphogenesis. However, the precise molecular mechanisms of PI3K activation and its downstream signalling in neurons remain elusive. Here, we report the identification of the Neuronal tYrosine-phosphorylated Adaptor for the PI 3-kinase (NYAP) family of phosphoproteins, which is composed of NYAP1, NYAP2, and Myosin16/NYAP3. The NYAPs are expressed predominantly in developing neurons. Upon stimulation with Contactin5, the NYAPs are tyrosine phosphorylated by Fyn. Phosphorylated NYAPs interact with PI3K p85 and activate PI3K, Akt, and Rac1. Moreover, the NYAPs interact with the WAVE1 complex which mediates remodelling of the actin cytoskeleton after activation by PI3K-produced PIP 3 and Rac1. By simultaneously interacting with PI3K and the WAVE1 complex, the NYAPs bridge a PI3K-WAVE1 association. Disruption of the NYAP genes in mice affects brain size and neurite elongation. In conclusion, the NYAPs activate PI3K and concomitantly recruit the downstream effector WAVE complex to the close vicinity of PI3K and regulate neuronal morphogenesis.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Myosin XVI binds directly to F-actin and also regulates stress fiber remodeling in fibroblasts and neurite outgrowth in neurons via its interaction with phosphatidylinositol 3-kinase (PI3K) and the WAVE complex 129 . Genetic association between the MYO16 gene and autism has been found in two large cohorts (AGRE and ACC) of European ancestry and replicated in two other major cohorts (CAP and CART) 130 , as well as in other studies [131][132][133][134] .…”

Fine Mapping on Chromosome 13q32–34 and Brain Expression Analysis Implicates MYO16 in Schizophrenia

“…Earlier evidence suggested that MYO16 is important for neuronal migration and brain development (Patel et al, 2001). More recently, MYO16 has been implicated in neuronal phosphoinositide 3-kinase (PI3K) signaling (Yokoyama et al, 2011), an extensively studied pathway involved in neuronal function and morphogenesis, as well as in a number of neurological and psychiatric disorders, including schizophrenia and autism (Waite and Eickholt, 2010). MYO16 is a member of the neuronal tyrosine-phosphorylated adaptor for the PI3K (NYAP) family of phosphoproteins, which is comprised of NYAP1, NYAP2, and Myo16/NYAP3.…”

“…In addition, NYAPs interact with the WAVE1 complex, thus serving as a bridge for a PI3K-WAVE1 interaction, which mediates PI3K-dependent remodeling of the actin cytoskeleton. Importantly, disruption of the NYAP genes in mice affects brain size and neurite elongation (Yokoyama et al, 2011). Notably, meta-analysis of the SAF2, GAIN, and MGS data sets (a total of 2956 cases) showed a gene-wise significant association (p-value of 1.8 Â 10 À 5 ) with a SNP located within the third intron of the NYAP2 gene (rs1897227), suggesting that variation within this gene family may be modulating the risk of schizophrenia (data not shown).…”

“…One SNP showed replicated association in one of the two independent samples and remained significant after meta-analysis and correction for multiple testing. This SNP is located within the MYO16 (myosin XVI) gene (Patel et al, 2001;Yokoyama et al, 2011). Second, we performed a comprehensive fine-scale mapping of the genetic contribution of this gene with respect to common variation, by genotyping an independent set of families from the Afrikaner population for 102 SNPs within MYO16 and by imputing the rest of the HapMap SNPs within the gene boundaries.…”

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

“…In its active dephosphorylated form, WAVE--1 initiates actin polymerization and thus facilitates neurotransmitter--induced neurite outgrowth and neuronal plasticity [189]. Neuronal tyrosine--phosphorylated adaptors for the phosphoinositide 3--kinase (NYAP) family of phosphoproteins have been identified as interaction partners of the WAVE--1 complex in developing neurons [190]. The ternary complex of phosphoinositide 3--kinase (PI3K), NYAPs and the WAVE--1 complex is recognized as another example of spatial and temporal control of signaling components to subcellular compartments in close vicinity of PI3K for regulation of neuronal morphogenesis [191].…”