The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway

Abstract

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.

YAP 1‐ LATS 2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis

“…Elevated YAP expression has been observed in many types of human cancers, including cancer of lung, liver, ovary, cervix, colon, and others [1,6,9,[16][17][18][19][20][21][22]. Consistently, the upstream tumor suppressors of the Hippo pathway, such as NF2 and LATS1/2, are frequently deleted or mutated in many malignancies [23,24]. Although mutations of YAP/TAZ are rare, a recent study reported that a germline point mutation of YAP (R331W) is correlated with a significantly higher incidence of lung carcinomas [25].…”

Fission yeast NDR/LATS kinase Orb6 regulates exocytosis via phosphorylation of exocyst complex

“…NDR kinases such as Trc (Drosophila), NDR1 and NDR2 (NDR1/2; mammals), and SAX-1/SAX-2 (C. elegans) share evolutionarily conserved functions in coordinating neurite branching and patterning of neuronal fields 10 . Other NDR kinases such as Wts (Drosophila), LATS1 and LATS2 (LATS1/2; mammals) and WTS-1 (C. elegans) regulate polarized differentiation of epithelia and other cell types 11 . In budding yeast S. cerevisiae and fission yeast S. pombe, NDR kinases Cbk1 and Orb6 (respectively) are required for polarized cellular morphogenesis [12][13][14] .…”

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

“…In the context of the Hippo pathway Lats1 and Lats2 are considered redundant, but each paralog also has unique functions such as estrogen-mediated signaling and p53 regulation, respectively. Furthermore, Lats kinases and Yap have ancient and conserved non-Hippo functions in spindle-assembly checkpoints and cytokinesis 51 . TRULI also offers the ability to investigate these non-Hippo functions of Lats kinases, and it would be prudent to understand the implications of Lats inhibition on these pathways prior to therapeutic endeavors.…”