AFAP1L2 (also known as XB130) is an adaptor protein that functions as a key regulator of SRC kinase activity and multiple signaling cascades. Structurally, it contains protein-binding modules enabling interactions with diverse signaling proteins 1. AFAP1L2 enhances SRC-dependent phosphorylation and activates the PI3K-AKT pathway through tyrosine phosphorylation-dependent association with the p85 regulatory subunit of PI3K 2. In oligodendrocyte differentiation, AFAP1L2 functions downstream of the PTN-PTPRZ signaling axis to activate PI3K-AKT-mTOR signaling and promote myelin protein expression 3. In cancer biology, AFAP1L2 overexpression promotes tumor progression across multiple cancer types. In hepatocellular carcinoma, elevated AFAP1L2 expression correlates with poor overall survival and drives sorafenib resistance by activating SRC-dependent FUNDC1 signaling that inhibits mitophagy 4. Similarly, AFAP1L2 overexpression promotes cholangiocarcinoma aggressiveness through PI3K/Akt pathway activation, correlating with lymph node metastasis and advanced TNM staging 5. Genetic studies demonstrate that AFAP1L2 variants show epistatic interaction with TERF1 loci, influencing melanoma risk through telomere biology pathways 6. AFAP1L2 expression is also modulated by SARS-CoV-2 infection, with hypermethylation detected months post-infection 7. These findings establish AFAP1L2 as a multifunctional adaptor with significant roles in both physiological differentiation and pathological tumorigenesis.