Elsevier

Seminars in Cancer Biology

Volume 48, February 2018, Pages 104-114
Seminars in Cancer Biology

Review
The NDR/LATS protein kinases in immunology and cancer biology

https://doi.org/10.1016/j.semcancer.2017.04.010Get rights and content

Abstract

The NDR (nuclear Dbf2-related)/LATS (large tumour suppressor) family of kinases represents a subclass of the AGC (protein kinase A (PKA)/PKG/PKC-like) group of serine/threonine protein kinases. Members of the NDR/LATS family are vital components of conserved pathways controlling essential cellular processes, such as proliferation (cell cycle progression) and cell death. In particular, the central involvement of NDR/LATS as YAP/TAZ kinases in the Hippo tissue growth control pathway has gained much interest. In this review, we summarise the roles of mammalian NDR1/2 (aka STK38/STK38L) and LATS1/2 in immunity and cancer biology. We also discuss the activation mechanisms of NDR/LATS involving Ste20-like kinases and the MOB1 signal transducer, followed by an overview of NDR/LATS knockout mouse models. We further review the mutation and expression status of NDR/LATS in human cancers and their possible predictive and/or prognostic value in cancer treatment.

Introduction

Protein kinases constitute one of the largest and most functionally diverse gene families [1], being key regulators of various biological processes that when deregulated can result in diseases such as cancer [2]. The catalytic domains of protein kinases act by chemically modifying their target proteins (substrates) through phosphorylation, which in turn can regulate the activities, subcellular localisation and overall function of many proteins. In particular, members of the serine (Ser)/threonine (Thr) AGC (protein kinase A (PKA)/PKG/PKC-like) class of protein kinases play well-understood signalling roles in the regulation of numerous essential and disease-associated processes [3], and hence their regulation and suitability for drug development have been explored [4].

AGC kinases come in the form of more than 70 distinctive, but similar, protein kinases, which are highly conserved throughout the eukaryotic kingdom, having been classified into several subgroups [1]. Based on their involvement in the Hippo tumour suppressor pathway, members of a subgroup of the AGC group of protein kinases termed the NDR (nuclear Dbf2-related)/LATS (large tumour suppressor) family of kinases have been studied more intensively over the past decade [5], [6], [7]. NDR/LATS kinases serve as tumour suppressor proteins in the Hippo pathway, although evidence has started to accumulate suggesting that they can also play context-dependent pro-growth and pro-survival roles in cancer cells. However, before we summarise these recent findings in the main section of the review, we will briefly define the unique characteristics of NDR/LATS kinases, followed by a short overview of the roles of NDR/LATS kinases in yeast and invertebrates.

Like most AGC kinases, NDR/LATS kinases need to be phosphorylated on two residues to achieve full kinase activation. These two phosphorylation events occur on the activation loop (aka T-loop) and the hydrophobic motif (HM) located centrally in the catalytic domain and C-terminally outside of the catalytic domain, respectively [3], [6]. In the case of human NDR/LATS kinases, a Ser residue in the T-loop and a Thr residue in the HM (Ser281/Ser282 and Thr444/Thr442 in human NDR1/2 and Ser909/Ser872 and Thr1079/Thr1041 in human LATS1/2, respectively) must be phosphorylated for full activation [5], [6], [7], [8]. Notably, all NDR/LATS kinases share two unique characteristics, a conserved N-terminal regulatory domain (NTR) in proximity to the catalytic domain and an insertion between subdomains VII and VIII of the catalytic domain [6]. Intriguingly, both unique domains play roles in the regulation of NDR/LATS kinases, with the NTR being required for co-activator binding, and hence kinase activation, while mutations of positively charged residues in the insertion can cause constitutive activation (at least in the case of NDR1/2 kinases, thus the insertion is also known as auto-inhibitory sequence [9]).

The NDR/LATS family is highly conserved from yeast to man [6]. In yeast and invertebrates, members of the NDR/LATS family are involved in the regulation of a broad-spectrum of cellular processes, including mitotic exit, cell proliferation and apoptosis (summarised in refs. [6], [10], [11]). Genetic studies demonstrated that yeast NDR/LATS kinases play central roles in controlling the mitotic exit network (MEN) and septation initiation network (SIN) in budding and fission yeast, respectively. In addition, other yeast NDR/LATS kinases are required for the regulation of morphogenesis through RAM (regulation of Ace2 and morphogenesis) and other processes. In Caenorhabditis elegans, the worm NDR kinase is likewise important for morphogenesis in the context of mechanosensory tiling in sensory dendrites. In Drosophila melanogaster, the fly NDR/LATS kinases Warts and Tricornered (Trc) are also key players in the regulation of neurite outgrowth and morphology. More importantly, fly genetics linked Warts to the regulation of tissue growth control through the Hippo pathway. In mammals, four NDR/LATS kinases display sometimes overlapping and other times completely distinct functions. NDR1 (aka STK38; Ser/Thr kinase 38), NDR2 (aka STK38L), LATS1 (large tumour suppressor 1) and LATS2 are expressed from different genes, hence having the potential to be regulated in completely different fashions.

Although the core components of the Hippo pathway were originally defined in yeast [6], our key understanding of the Hippo pathway was driven by fly genetics (summarised in refs. [12], [13], [14]). In summary, the Ste20-like Hippo kinase was shown to activate the fly NDR/LATS kinase Warts, which in turn bound to scaffolding proteins such as Mats (MOB1 as tumour suppressor) phosphorylates and thereby inhibits the co-transcriptional activator Yorkie (Yki), which when deregulated promotes tissue growth through binding to transcription factors such as Scalloped to drive pro-survival and pro-growth transcriptional programmes (Fig. 1A). Like genetic inactivation of hippo, warts or mats, the overexpression of Yki significantly causes robust tissue overgrowth, with Yki functioning as a major downstream effector of Hippo signalling in flies.

In mammals, the functional counterparts of Hippo, Warts, Mats, Yki and Scalloped can also be classified as tumour suppressor proteins or proto-oncoproteins. Mammalian MST1/2 (mammalian Ser/Thr sterile 20 (Ste20)-like kinases 1/2), LATS1/2, MOB1 (Mps one binder 1), YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif) and TEADs (TEA domain proteins) correspond to fly Hippo, Warts, Mats, Yki and Scalloped, with human MST2 [15], LATS1 [16], [17] and MOB1A [18] being able to rescue loss-of-function phenotypes of hippo, warts and mats mutants, respectively. Similar to Drosophila, MST1/2-activated LATS1/2, in complex with MOB1, phosphorylates and thereby inhibits YAP/TAZ [19], [20], [21], [22], [23], [24], [25], [26], [27] (Fig. 1B). In this regard, recent findings indicate that NDR1/2 kinases should also be considered as novel members of this Hippo core cassette [5], [28]. Specifically, like LATS1/2, NDR1/2 can function downstream of Ste20-like kinases, are regulated by MOB1 binding and most importantly can act as YAP kinases. Human NDR1 can also rescue loss-of-function phenotypes in trc mutants [29]. However, it is noteworthy that NDR/LATS kinases can display a functional separation. For example, although cancer/growth-related functions have been attributed to Wts, no such functions are yet to be described for Trc in Drosophila [5].

In summary, unlike any other AGC kinase, NDR/LATS have unique and highly distinctive features. Members of the NDR/LATS family have important biological functions in uni- and multi-cellular organisms such as yeast and invertebrates. In this review, we focus on summarising the roles of mammalian NDR/LATS kinases in immunology and cancer biology, although mammalian NDR/LATS signalling is also significant for other crucial processes. For example, NDR1/2 have important cellular functions in neurobiology [5] and LATS1/2 in heart development and homeostasis [30], [31]. Therefore, we refer the reader to other references cited herein to obtain a complete overview of all roles of NDR/LATS signalling in mammals. Where suitable, we will mention discoveries made in Drosophila, although we recommend consulting other reviews for more comprehensive summaries of the fly Hippo pathway [13], [32], [33], [34].

Section snippets

Updated view on the regulation of NDR/LATS kinases

As briefly outlined above, NDR/LATS kinases can be regulated by MST1/2. More precisely, MST1/2 phosphorylate NDR1/2 and LATS1/2 on their specific Thr residue located in the HM (summarised in ref. [5]). Similarly, Hippo phosphorylates Trc and Warts on their HM phosphorylation regulatory sites in flies [35]. Additionally, the MST3 kinase, another Ste20-like kinase that is closely related to MST1/2 [36], can phosphorylate NDR1/2 on their HMs [37], [38], while MST3 does not seem to phosphorylate

Competing interest

The authors declare that they have no commercial or other competing interests to disclose.

Acknowledgements

We apologise to all scientists whose studies could not be included due to space constraints. We are very grateful to Joanna Lisztwan and all members of the Hergovich laboratory for their critical reading of the manuscript. The Hergovich laboratory has been supported by the Wellcome Trust (090090/Z/09/Z), BBSRC (BB/I021248/1), Worldwide Cancer Research (AICR; 11-0634), UCL Cancer Research UK Centre funding, and the National Institute for Health Research University College London Hospitals

References (227)

  • Y. Hao et al.

    Tumor suppressor LATS1 is a negative regulator of oncogene YAP

    J. Biol. Chem.

    (2008)
  • C.-Y. Liu et al.

    The Hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCFβ-TrCP E3 ligase

    J. Biol. Chem.

    (2010)
  • W. Huang et al.

    The N-terminal phosphodegron targets TAZ/WWTR1 protein for SCFβ-TrCP-dependent degradation in response to phosphatidylinositol 3-kinase inhibition

    J. Biol. Chem.

    (2012)
  • L. Zhang et al.

    NDR functions as a physiological YAP1 kinase in the intestinal epithelium

    Curr. Biol.

    (2015)
  • I. Dan et al.

    The Ste20 group kinases as regulators of MAP kinase cascades

    Trends Cell Biol.

    (2001)
  • Y. Zheng et al.

    Identification of Happyhour/MAP4K as alternative Hpo/Mst-like kinases in the Hippo kinase cascade

    Dev. Cell

    (2015)
  • S.W. Plouffe et al.

    Characterization of Hippo pathway components by gene inactivation

    Mol. Cell

    (2016)
  • A. Hergovich

    MOB control: reviewing a conserved family of kinase regulators

    Cell. Signal.

    (2011)
  • D. Cook et al.

    Constitutively active NDR1-PIF kinase functions independent of MST1 and hMOB1 signalling

    Cell. Signal.

    (2014)
  • M. Praskova et al.

    MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation

    Curr. Biol.

    (2008)
  • A.M. Vrabioiu et al.

    Fat/dachsous signaling promotes Drosophila wing growth by regulating the conformational state of the NDR kinase warts

    Dev. Cell

    (2015)
  • A. Hergovich et al.

    The MST1 and hMOB1 tumor suppressors control human centrosome duplication by regulating NDR kinase phosphorylation

    Curr. Biol.

    (2009)
  • S.A. Manning et al.

    Warts opens up for activation

    Dev. Cell

    (2015)
  • A. Hergovich et al.

    The human tumour suppressor LATS1 is activated by human MOB1 at the membrane

    Biochem. Biophys. Res. Commun.

    (2006)
  • F. Yin et al.

    Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2

    Cell

    (2013)
  • C. Rauskolb et al.

    Cytoskeletal tension inhibits Hippo signaling through an Ajuba-Warts complex

    Cell

    (2014)
  • W. Li et al.

    Merlin/NF2 loss-Driven tumorigenesis linked to CRL4 DCAF1-mediated inhibition of the Hippo pathway kinases lats1 and 2 in the nucleus

    Cancer Cell

    (2014)
  • P.M. Voorhoeve et al.

    A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors

    Cell

    (2006)
  • B.J. Thompson et al.

    The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila

    Cell

    (2006)
  • R. Nolo et al.

    The bantam microRNA is a target of the Hippo tumor-suppressor pathway

    Curr. Biol.

    (2006)
  • M. He et al.

    New insights into posttranslational modifications of Hippo pathway in carcinogenesis and therapeutics

    Cell Div

    (2016)
  • N. Yabuta et al.

    Lats2 is an essential mitotic regulator required for the coordination of cell division

    J. Biol. Chem.

    (2007)
  • K. Cockburn et al.

    The Hippo pathway member Nf2 is required for inner cell mass specification

    Curr. Biol.

    (2013)
  • D. Zhou et al.

    Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene

    Cancer Cell

    (2009)
  • D. Yimlamai et al.

    Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer

    J. Hepatol.

    (2015)
  • C. Joffre et al.

    The pro-apoptotic STK38 kinase is a new Beclin1 partner positively regulating autophagy

    Curr. Biol.

    (2015)
  • E. Devroe et al.

    HIV-1 incorporates and proteolytically processes human NDR1 and NDR2 serine-threonine kinases

    Virology

    (2005)
  • C. Atkins et al.

    Global human-Kinase screening identifies therapeutic host targets against influenza

    J. Biomol. Screen.

    (2014)
  • G. Manning et al.

    The protein kinase complement of the human genome

    Science

    (2002)
  • L.R. Pearce et al.

    The nuts and bolts of AGC protein kinases

    Nat. Rev. Mol. Cell Biol.

    (2010)
  • A. Hergovich

    The roles of NDR protein kinases in Hippo signalling

    Genes

    (2016)
  • A. Hergovich et al.

    NDR kinases regulate essential cell processes from yeast to humans

    Nat. Rev. Mol. Cell Biol.

    (2006)
  • A. Hergovich

    Regulation and functions of mammalian LATS/NDR kinases: looking beyond canonical Hippo signalling

    Cell Biosci.

    (2013)
  • A. Hergovich

    Hippo signaling in mitosis: an updated view in light of the MEN pathway

    Mitotic Exit Network: Methods Protoc.

    (2017)
  • S. Sun et al.

    Cellular organization and cytoskeletal regulation of the Hippo signaling network

    Trends Cellbiol.

    (2016)
  • B.K. Staley et al.

    Hippo signaling in Drosophila: recent advances and insights

    Dev. Dyn.

    (2012)
  • W. Tao et al.

    Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity

    Nat. Genet.

    (1999)
  • T. Yu et al.

    Evidence for a tumor suppressor role for the large tumor suppressor genes LATS1 and LATS2 in human cancer

    Genetics

    (2013)
  • J. Zhang et al.

    Negative regulation of YAP by LATS1 underscores evolutionary conservation of the Drosophila Hippo pathway

    Cancer Res.

    (2008)
  • B. Zhao et al.

    Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

    Genes. Dev.

    (2007)
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