PRRG4 (proline rich and Gla domain 4) is a transmembrane protein that functions primarily as a regulator of axon guidance and cell migration through its control of the ROBO1 receptor. PRRG4 acts as a functional homolog of the Drosophila commissureless protein, preventing ROBO1 delivery to the cell surface and promoting its degradation 1. The protein contains characteristic PY motifs and WW binding domains that enable protein-protein interactions 2. Mechanistically, PRRG4 recruits the E3 ubiquitin ligase NEDD4 through its LPSY and PPPY motifs, leading to ubiquitination and degradation of ROBO1, which subsequently activates Src and FAK signaling pathways 3. PRRG4 has significant disease relevance, particularly in cancer and neurodevelopmental disorders. In breast cancer, elevated PRRG4 expression promotes metastasis through ROBO1 downregulation 3. The gene is located within the WAGR syndrome critical region, and haploinsufficiency of PRRG4 may contribute to the severe developmental delays and autistic behaviors characteristic of this syndrome 4. Clinically, PRRG4 shows promise as a potential biomarker and therapeutic target for metastatic breast cancer 3 and may serve as a prognostic marker in esophageal adenocarcinoma 5.