PDF《Hippo pathway》

Review The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway Noa Furth1 and Yael Aylon*,1 Proper cellular functionality and homeostasis are maintained by the convergent integration of various signaling cascades, which enable cells to respond to internal and external changes.

The Dbf2-related kinases LATS1 and LATS2 (LATS) have emerged as central regulators of cell fate, by modulating the functions of numerous oncogenic or tumor suppressive effectors, including the canonical Hippo effectors YAP/TAZ, the Aurora mitotic kinase family, estrogen signaling and the tumor suppressive transcription factor p53. While the basic functions of the LATS kinase module are strongly conserved over evolution, the genomic duplication event leading to the emergence of two closely related kinases in higher organisms has increased the complexity of this signaling network. Here, we review the LATS1 and LATS2 intrinsic features as well as their reported cellular activities, emphasizing unique characteristics of each kinase. While differential activities between the two paralogous kinases have been reported, many converge to similar pathways and outcomes. Interestingly, the regulatory networks controlling the mRNA expression pattern of LATS1 and LATS2 differ strongly, and may contribute to the differences in protein binding partners of each kinase and in the subcellular locations in which each kinase exerts its functions. Cell Death and Differentiation (2017) 24, 1488C1501;

doi:10.1038/cdd.2017.99;

published online

23 June

2017 Facts LATS1 and LATS2 proteins show extensive sequence similarity and share similar modes of post-translational modifications. The LATS genes are differentially regulated at the transcriptional level. LATS kinases engage divergent binding partners, although these effectors often converge on similar cellular processes. Whole-body deletion, as well as tissue-specific deletion, of either Lats1 or Lats2, reveals critical differences in the in vivo functions of the two kinases. Open Questions Additional signaling pathways: what other functions do LATS kinases have beyond restricting YAP/TAZ activity? Redundant versus divergent function: what is the contribu- tion of each kinase to distinct biological processes? Phosphorylation substrates of LATS: how is LATS kinase target recognition determined beyond simple amino-acid sequence motifs? Pro- versus anti-tumor effects: how does cellular context direct LATS toward apparently opposing functional outcomes? In recent years, the LATS1 and LATS2 kinases have become the focus of intense research interest. They are gaining prominence due to their broad range of biological activities in cell cycle regulation, differentiation and motility, as well as the diverse pathological outcomes of their deregulation. LATS kinases are critical for organism fitness, genome integrity and cancer prevention. The core kinase module is evolutionarily conserved from yeast through flies to humans, although effectors and biological impact have expanded over the course of evolution. The yeast ortholog of LATS, Dbf2 is localized to the spindle pole body (yeast centrosome) and regulates mitotic exit.1 Cdc15 (homolog of MST) is required for Dbf2 activation,2,3 and together they constitute a kinase module of the mitotic exit network.1,3 This module has been conserved in humans, manifested by LATS phosphorylation and activation by MST1/2 (MST) kinases.4 During evolution, this module recruited numerous different effectors, most notably the transcriptional coactivators YAP and TAZ, and extended its repertoire of biological functions. The Caenorhabditis elegans LATS, Ce-Wts-1, is associated with development, lifespan and body length control.5 Interestingly, nematodes lack YAP/TAZ,6 and Ce-Wts-1 exerts its function via effectors of the TGF-beta signaling pathway.5 Deletion of the Drosophila Warts (Wts, the fly ortholog of LATS) causes dramatic tissue overgrowth and abnormalities in cellular polarity.7,8 The fly Warts-Hippo (Hpo, MSTortholog) module exerts some of its functions via phosphorylation and inhibition of Yorkie (Yki, YAP and TAZ ortholog),9 while maintaining ancestral Yki-independent functions.10 The strong evolutionary conservation of the MST/LATS/YAP cascade (the Hippo pathway) is exemplified by the fact that human LATS