TRAF2 is an E3 ubiquitin-protein ligase that functions as a critical signaling adaptor regulating cell survival and death through multiple pathways. Primary Function: TRAF2 catalyzes K63-linked ubiquitination of key substrates including RIPK1, MLST8, IKBKE, and beclin 1, serving as an essential component of E3 ubiquitin-protein ligase complexes 12. Mechanism: TRAF2 promotes NF-κB and JNK activation through K63-polyubiquitination of RIPK1, facilitating survival signaling downstream of TNF receptors and CD40 34. Additionally, TRAF2 regulates mTORC1/mTORC2 assembly and modulates autophagy through K63-ubiquitination of MLST8 and beclin 1 25. TRAF2 also regulates Wnt/β-catenin signaling by interacting with β-catenin, supporting cancer cell proliferation 6. Disease Relevance: TRAF2 dysregulation contributes to multiple pathologies. In doxorubicin-induced cardiotoxicity, TRAF2 proteasomal degradation impairs TNFα-NF-κB survival signaling, promoting cardiomyocyte death 3. In cancers, TRAF2 upregulation promotes colon, renal, and hepatocellular carcinoma progression through Wnt signaling, M2 macrophage infiltration, and mTORC1 activation 678. Conversely, TRAF2 deletion enhances tumor sensitivity to immunotherapy and exhibits anti-viral activity in HIV infection 910. Clinical Significance: TRAF2 represents a therapeutic target; modulation strategies include pharmacological TRADD inhibition for neurodegenerative diseases and selective TRAF2 targeting for cancer therapy.