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Abstract

The Large Tumor Suppressor 1 and 2 (LATS1 and LATS2) were originally identified as core effectors of the Hippo signaling pathway, directly regulating the oncogenes YAP and TAZ. However, intense research in recent years has implicated the two kinases LATS1 and LATS2 in a number of functions outside this pathway, such as cell cycle regulation, maintenance of genome stability, or the control of cell proliferation, differentiation, and apoptosis. In addition, the expression levels of LATS1 and LATS2 are downregulated in many cancers, indicative of their role as tumor suppressors, as reflected in their naming. Since both paralogues are involved in the same biological processes, they have long been considered functionally redundant. However, there is emerging evidence that unique features of LATS1 and LATS2 could account for potential differences in protein function. Yet, little is known about the mechanism through which LATS1 and LATS2 operate, and in particular their direct kinase targets. In the present study, different knockdown and overexpression cell systems derived from female breast tissue were established, allowing for individual manipulations of LATS1 or LATS2 protein levels. As a read-out for LATS1- or LATS2-induced cell signaling, in-depth multi-layered MS-based proteomics, including global proteome, translatome, and phosphoproteome analysis, was applied. The data generated from a luminal B breast cancer cell line supports the hypothesis of a novel cell cycle arrest in late anaphase, induced by LATS1 and LATS2 overexpression. Furthermore, data from a non-tumorigenic cell line supports the hypothesis that LATS1 and LATS2 can act as promotors of the cell cycle besides their known roles as tumor suppressors. Additionally, the present study allows for novel insights into (i) the role of LATS1 and LATS2 in cell cycle regulation, underlined by interaction networks between LATS1/2 and the APC/C complex, or the Aurora kinases, (ii) their cross-talk with other tumor suppressors such as RUNX3 and p53, (iii) their interplay with signaling pathways such as the cell polarity pathway (PCP), or the SLIT/ROBO signaling, and (vi) potential candidates for LATS1- and LATS2-substrates. Together, this study provides rich datasets of LATS1/2-mediated effects on cell signaling, as well as potentially novel LATS1/2 kinase substrates which will support the understanding and in-depth characterization of these tumor suppressors, and facilitate the identification of cancer vulnerabilities.