SH3RF3 is an E3 ubiquitin-protein ligase with E3 ubiquitin-protein ligase activity and protein autoubiquitination capacity [GO annotations]. Beyond its canonical ubiquitin ligase function, SH3RF3 operates as a scaffold protein essential for presynaptic function. It facilitates complex formation between kinase BRSK1/SAD-B and the ASD-associated protein RIM1, regulating synaptic vesicle docking and readily releasable pool size 1. SH3RF3 also activates JNK signaling in a JNK-interacting protein-dependent manner, promoting cancer stem-like cell properties through PTX3 upregulation 2. Regulation of SH3RF3 occurs at multiple levels: miR-192-5p suppresses SH3RF3 expression by binding its 3'UTR, thereby inhibiting cancer cell proliferation and migration 3, while circNFIX enhances SH3RF3 mRNA stability via LIN28B recruitment, promoting ovarian cancer stemness 4. Disease relevance is substantial: SH3RF3 deficiency causes autism-like behaviors through impaired excitatory-inhibitory balance in the prefrontal cortex 1. DNA methylation at SH3RF3 associates with anxiety disorder treatment response to cognitive behavioral therapy 5. Additionally, SH3RF3 variants associate with fasting insulin levels in children, potentially linking metabolic and neurodegenerative traits 6, and modify age at onset in familial Alzheimer disease 7. SH3RF3 expression marks high-plasticity breast cancer subtypes 8, positioning it as both a diagnostic and therapeutic target.