PTEN Regulation by WWP2

Abstract

WWP2 is a member of NEDD4 family HECT E3 ubiquitin ligases. The architecture of the NEDD4 family proteins include an N‐terminal C2 domain, two to four WW domains, and a C‐terminal HECT catalytic domain. The NEDD4 family E3 ligases play important regulatory roles in development and differentiation, immunological function, and cancer development, and their activity needs to be tightly regulated to prevent pathogenesis. WWP2 is the E3 ligase that catalyzes Lys ubiquitination of numerous proteins including key transcription factors such as OCT4 and signaling molecules such as PTEN. Our lab has been interested in studying how PTEN C‐tail phosphorylation (residues Ser380, Thr382, Thr383, and Ser385) regulates its ubiquitination by WWP2. Using expressed protein ligation, we generated semisynthetic non‐phosphorylated and tetra‐phosphorylated PTEN, and found that the non‐phosphorylated PTEN is more efficiently ubiquitinated by WWP2 than the phosphorylated PTEN, indicating that C‐tail phosphorylation of PTEN could inhibit its ubiquitination by WWP2. In the course of our studies, we have found that WWP2 itself is regulated by autoinhibition. We have dissected aspects of WWP2 that contribute to its autoinhibition and will discuss how the protein may be regulated to ensure proper catalytic tone.