We performed a comprehensive analysis of a literature-mined human signaling network by integrating data on ubiquitin-mediated protein half-lives. We found that proteins with very long half-lives are connected to form a network backbone, while proteins with short and medium half-lives preferentially attach to the network backbone and scatter throughout the network. Furthermore, proteins with short and medium half-lives are mutually exclusive in network neighbors. Short half-life proteins are enriched in the upstream portion of the network, suggesting that ubiquitination might help initiate signal processing and specificity. We also discovered that ubiquitination preferentially occurs in positive regulatory loops. Furthermore, these loops predominately induce or positively regulate apoptosis, a major component in cancer signaling. These results lead us to discover that the highly expressed genes involved in the common machinery of ubiquitination, the 26S proteasome genes, are significantly correlated with tumor progression and metastasis. Furthermore, expression of the 26S proteasome gene set predicts the clinical outcome of breast cancer patients. Our findings have implications for the development of cancer treatments and prognostic markers focused on the ubiquitination machinery.