Protein-protein interaction (PPI) is a fundamental form of communication within the cell that facilitates the initiation or inhibition of distinct cellular processes based on the current intracellular and extracellular environment. A particular network of dynamic PPI’s that transmits a signal and results in a specific cellular process is viewed as a signaling pathway. The total PPI network of a protein is commonly referred to as an interactome. Protein interactomes can provide substantial insight into the molecular mechanisms behind a cellular process, aid in identifying the molecular function of a protein of interest (POI), and elucidate how signaling pathways are altered during disease progression. Proteins or genes involved in the development or progression of cancer are said to be oncogenic and are the central focus of oncology. The RAS signaling pathway is the most frequently altered and one of the most well studied oncogenic networks in cancer. Each of the four RAS isoforms, HRas, NRas, KRas4A and KRas4B have been found to be preferentially activated in distinct cancer types suggesting they have distinct PPI networks. This prompted us to employ a comparative and quantitative proteomics approach to generate isoform-specific interactomes of the four RAS isoforms. Many isoform-specific interacting proteins were identified including HRAS-specific CARM1 and CHK1, and KRAS-specific PIP4K2C and IPO7. These interacting proteins play important roles as knockdown or pharmacological inhibition leads to potent inhibition of cancer cells. The HRAS-specific interacting protein CARM1 plays a role in HRAS-induced senescence, with CARM1 knockdown or inhibition selectively increases senescence in HRAS-transformed cells but not KRAS4B-transformed cells. Revealing new isoform-specific RAS interactors aids in understanding the overlapping functions of the RAS isoforms. BZW2 (basic leucine zipper and W2 domains 2) is a lesser-known protein with an emerging oncogenic role. Since 2017, it has been reported to promote the progression of acute myeloid leukemia, multiple myeloma, throat, bone, bladder, colorectal, pancreatic, and liver cancer. Yet, little is known about the molecular mechanisms behind these observations. To gain insight into BZW2 molecular functions, we used quantitative proteomics to create a high-confidence interactome. We found that BZW2 interacts with both endoplasmic reticulum (ER) and mitochondrial proteins. We thus hypothesized that BZW2 localizes to and promotes the formation of ER-mitochondrial contact sites, and that such localization would promote calcium transport from ER to the mitochondria and boost mitochondrial metabolism. Indeed, we found that BZW2 localized to ER-mitochondria contact sites and that BZW2 knockdown decreased ER-mitochondrial contact, mitochondrial calcium levels, and mitochondrial ATP production. These findings provide key insights into molecular functions of BZW2, the potential role of BZW2 in cancer progression, and highlights the utility of interactome data in understanding the function of less-studied proteins.