AGAP3 (ArfGAP with GTPase domain, ankyrin repeat and PH domain 3) is a multifunctional signaling protein with GTPase-activating protein activity for ADP ribosylation factors. Primary function: AGAP3 is an essential component of the NMDA receptor signaling complex that links NMDA receptor activation to AMPA receptor trafficking during long-term potentiation, regulating both Ras/ERK and Arf6 signaling pathways 1. It also interacts with microtubule-associated proteins within the CLASP2 protein network 2. Mechanism: AGAP3 contains multiple signaling domains including a GTPase-like domain, pleckstrin homology domain, and ArfGAP domain. A splicing variant, CRMP5-associated GTPase (CRAG), upregulates c-Jun expression and enhances cell proliferation through activator protein 1 activation 3. Disease relevance: AGAP3 is implicated in multiple malignancies. AGAP3 gene fusions with BRAF are present in melanoma and contribute to acquired vemurafenib resistance in BRAF V600E mutant tumors, though cells remain sensitive to MEK inhibitors 45. AGAP3 fusions with RET occur in Spitz neoplasms 6 and low-grade serous ovarian carcinomas 7. AGAP3 overexpression is significantly elevated in colorectal cancer compared to normal tissue 3. Clinical significance: Detection of AGAP3-BRAF fusions in melanoma may predict MEK inhibitor sensitivity, with documented long-term responses to combination BRAF/MEK inhibitor therapy 45.