Apicobasal surfaceome architecture encodes for polarized epithelial functionality and depends on tumor suppressor PTEN

The loss of apicobasal polarity during the epithelial-to-mesenchymal transition (EMT) is a hallmark of cancer and metastasis. The key feature of this polarity in epithelial cells is the subdivision of the plasma membrane into apical and basolateral domains, with each orchestrating specific intra- and extracellular functions. Epithelial transport and signaling capacities are thought to be determined largely by the quality, quantity and nanoscale organization of proteins residing in these membrane domains, the apicobasal surfaceomes. Despite its implications for cancer, drug uptake and infection, our current knowledge of how the polarized surfaceome is organized and maintained is limited. Here we used chemoproteomic surfaceome scanning to establish proteotype maps of apicobasal surfaceomes and reveal quantitative distributions of i.a. surface proteases, phosphatases and tetraspanins as potential key regulators of polarized cell functionality. We show further that tumor-suppressor PTEN regulates polarized surfaceome architecture and uncover a potential role in collective cell migration. Our differential surfaceome analysis provides a molecular framework to elucidate polarized protein networks regulating epithelial functions and PTEN-associated cancer progression. Summary One cell, two functionally different surfaceomes: Chemoproteomic surfaceome scanning reveals quantitative polarization of protein networks across the epithelial cell membrane and unrecognized roles of tumor suppressor PTEN in surfaceome organization associated with cancer progression.