CBL family proteins have been widely reported as negative regulators of various signal pathways, which determines the amplitude and duration of signaling response through mediating the ubiquitination and degradation of activated receptors. CBL and CBLB share high degrees of structural similarities, and they are more than just ubiquitin-protein ligases and contain rich interactive domains and motifs that nucleate the assembly of protein complex taking various cellular functions. However, proteome-wide interaction network mediated by CBL proteins was rarely reported. This study is aimed to explore CBL and CBLB-mediated interactomes, hoping to uncover their regulatory roles in EGFR signaling and provide new insight into the molecular events driving tumorigenesis. With the construction of stable HeLa cell lines inducibly expressing FLAG-tagged CBL or CBLB, we detected both stable interactomes and EGF stimulation-induced temporal interactomes of CBL and CBLB through AP-MS approach. Time-resolved profiling and functional annotations of the temporal interactomes sheds light on the dynamic assemble of signal proteins over the signal cascade. Moreover, comparison between interactomes of CBL and CBLB indicates the redundant but also complementary functions of them. This work offer a useful resource for CBL and CBLB interactome, highlighting their prominent and diverse roles in the EGFR signalsome.