SH3BP4 is a multifunctional adapter protein involved in endocytosis and signaling regulation. Structurally, it contains an SH3 domain, multiple NPF motifs, and a nuclear targeting signal 1, with broad tissue expression particularly in pancreas, placenta, heart, and kidney 1. Primary functions include regulating clathrin-mediated endocytosis of cargo receptors. SH3BP4 recruits neuropilin-1 and α5β1-integrin to clathrin-coated pits in a phosphorylation-dependent manner, with Akt-mediated phosphorylation at S246 preventing its CCP localization via 14-3-3 binding 2. It also mediates SARS-CoV-2 internalization through integrin- and clathrin-dependent pathways independent of ACE2 3. SH3BP4 acts as a negative regulator of TOR signaling by inhibiting active Rag GTPase complex formation 4, thereby modulating mTORC1 activity and autophagy. Additionally, it suppresses Wnt signaling through a zinc-finger ubiquitin-like domain (ZU5) that restricts β-catenin nuclear localization 5. Disease relevance includes intestinal stem cell regulation and tumorigenesis; Sh3bp4 loss increases ISC proliferation and accelerates Apc-driven adenoma development 5. SH3BP4 has been identified as a novel Alzheimer's disease-associated locus showing epistatic interaction with APOE, possibly conferring protective mechanisms 6. SH3BP4 is transcriptionally regulated by MITF and miR-125b in melanogenesis 7, though it shows no independent prognostic value in metastasis despite protein interaction with MACC1 8.