NDR2 kinase: A review of its physiological role and involvement in carcinogenesis

The Hippo kinase, NDR2, plays a key role in the natural history of several human cancers, particularly lung cancer, by regulating processes such as proliferation, apoptosis, migration, invasion, vesicular trafficking, autophagy, ciliogenesis and immune response. To examine the specificity of NDR2's action, interaction and function in physiological or tumoral contexts, we first focus on the structural differences in the amino-acid sequence between NDR1 and NDR2. We then establish a correlation between these NDR1/2 differences and specific post-translational regulation, as well as the distinct action, interactions, and functions of NDR2 in physiological or tumoral paradigms, such as lung cancer. Furthermore, the full set of NDR2 partners and/or substrates remains to be identified. Given that it is hypothesized that NDR2 and its partners may offer new perspectives for anticancer therapies, we emphasize potential clustering or functional enrichment networks among the NDR2-specific interactants. Additionally, we provide an unpublished proteomic comparison of the NDR1 versus NDR2 interactome, focusing on human bronchial epithelial cells (HBEC-3), lung adenocarcinoma cells (H2030), and their brain metastasis-derived counterparts (H2030-BrM3). In conclusion, this study underscores the pivotal role of NDR2 in cancer progression, particularly lung cancer, and helps to better understand their specific functions and interactions in both normal and tumor contexts. The identification of NDR2 partners and substrates remains essential, with the potential to open new avenues for anticancer therapies. • Despite high similarity to NDR1, NDR2 kinase has specific functions • NDR2 controls the trafficking of vesicles and the autophagy • NDR2 behaves like an oncogene in most cancers • NDR2-intractome highlights the processes supporting the lung cancer progression • NDR2 and its interactors represent potential new therapeutic targets for metastatic cancer