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

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 N euronal t Y rosine‐phosphorylated A daptor for the P I 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. NYAP is a newly identified protein family that governs actin remodelling and neurite outgrowth. NYAPs are phosphorylated by the tyrosine kinase Fyn, which enhances interaction with PI3K and the WAVE1 complex and thereby regulating the cytoskeleton.