PEAK3 is a catalytically inactive pseudokinase that functions as a regulatory scaffold protein to control cell motility and oncogenic signaling pathways 1. The protein operates through a conserved split helical dimerization (SHED) domain that enables both homo- and hetero-association with other PEAK family members, which is critical for its signaling function 21. PEAK3's primary mechanism involves binding to and antagonizing CRK-II signaling, preventing the formation of CRK-II-dependent membrane ruffling and lamellipodia-like extensions through dimerization-dependent interactions 1. The protein also activates oncogenic AKT signaling independent of growth factor stimulation and interacts with key signaling proteins including GRB2, ASAP1/2, and PYK2, with these interactions requiring an intact SHED domain 2. PEAK3 demonstrates oncogenic properties, as overexpression enhances cell growth and migration in sarcoma cells, while its silencing reduces these effects in leukemic cells 2. The protein is strongly expressed in hematopoietic cells and is upregulated in acute myeloid leukemia, suggesting clinical relevance in cancer progression 2. The integrity of both the SHED domain and the conserved DFG motif in the pseudokinase domain is essential for PEAK3's dimerization capacity and subsequent cellular functions 12.