Mammalian Hippo signalling: a kinase network regulated by protein-protein interactions
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
124 Biochemical Society Transactions (2012) Volume 40, part 1
Mammalian Hippo signalling: a kinase network
regulated by protein–protein interactions
Alexander Hergovich1
Tumour Suppressor Signalling Networks Laboratory, UCL Cancer Institute, University College London, London WC1E 6BT, U.K.
Abstract
The Hippo signal transduction cascade controls cell growth, proliferation and death, all of which are
frequently deregulated in tumour cells. Since initial studies in Drosophila melanogaster were instrumental
in defining Hippo signalling, the machinery was named after the central Ste20-like kinase Hippo. Moreover,
given that loss of Hippo signalling components Hippo, Warts, and Mats resulted in uncontrolled tissue
overgrowth, Hippo signalling was defined as a tumour-suppressor cascade. Significantly, all of the core
factors of Hippo signalling have mammalian orthologues that functionally compensate for loss of their
counterparts in Drosophila. Furthermore, studies in Drosophila and mammalian cell systems showed that
Hippo signalling represents a kinase cascade that is tightly regulated by PPIs (protein–protein interactions).
Several Hippo signalling molecules contain SARAH (Salvador/RASSF1A/Hippo) domains that mediate specific
PPIs, thereby influencing the activities of MST1/2 (mammalian Ste20-like serine/threonine kinase 1/2)
kinases, the human Hippo orthologues. Moreover, WW domains are present in several Hippo factors, and
these domains also serve as interaction surfaces for regulatory PPIs in Hippo signalling. Finally, the kinase
activities of LATS1/2 (large tumour-suppressor kinase 1/2), the human counterparts of Warts, are controlled
by binding to hMOB1 (human Mps one binder protein 1), the human Mats. Therefore Hippo signalling is
regulated by PPIs on several levels. In the present paper, I review the current understanding of how these
regulatory PPIs are regulated and contribute to the functionality of Hippo signalling.
Introduction (nuclear Dbf2-related) family of kinases have attracted more
Various molecular processes need to be deregulated in cancer attention due to their involvement in the regulation of cell
cells in order to ensure the long-term survival of cancerous division, genomic stability, cell growth, cell proliferation and
material. Hanahan and Weinberg recently updated their controlled cell death/apoptosis [4,5]. Research over the last
Hallmarks of Cancer review [1], pointing out that, in addition decade has revealed that LATS/NDR kinases are central
to hallmarks such as resistance to cell death, sustained parts of complex signal transduction cascades in multicellular
proliferative potential and evasion of growth suppression, eukaryotes [6–11].
researchers should also consider genomic instability as an Our current understanding of the regulation of these core
enabling characteristic, and deregulation of cellular energetics components can be briefly summarized as follows: members
as a novel emerging hallmark of cancer. Given the ongoing of the MST (mammalian Ste20-like serine/threonine) kinase
fight against human cancer, it is not surprising that intensive family activate LATS/NDR kinases by phosphorylation
research efforts are ongoing to understand signal transduction [5], a process which seems to require the PPI (protein–
machineries that play key roles in the control of all protein interaction) of LATS/NDR with members of the
these cancer-driving and/or -enabling cellular processes. MOB (Mps one binder) protein family [12]. Activated
Significantly, numerous signal transduction cascades transmit LATS/NDR kinases then target downstream factors such
extra- and intra-cellular inputs through protein kinases, as the proto-oncogene YAP [7,11] or the CDK (cyclin-
which represent one of the largest superfamilies found in the dependent kinase) inhibitor p21 protein [13] respectively.
human genome [2]. In particular, members of the AGC kinase In particular, MST/LATS/YAP signalling has attracted much
subfamily of protein kinases have diverse and crucial cellular attention, since deregulated expression of these components
functions that are deregulated in cancer cells [3]. Specifically, can result in cellular transformation [3,7,8,10,11].
members of a subgroup of the AGC group of protein Noteworthy studies in Drosophila were instrumental in
kinases termed the LATS (large tumour-suppressor)/NDR defining Hippo/Warts/Yorkie signalling (the counterpart of
human MST/LATS/YAP signalling), hence MST/LATS/YAP
signalling was named after the central Ste20-like kinase
Key words: Hippo signalling pathway, Mps one binder protein (MOB), phosphorylation, protein
kinase signal transduction, protein–protein interaction.
Hippo. Therefore I refer to MST/LATS/YAP signalling
Abbreviations used: AMOTL, angiomotin-like protein; HM, hydrophobic motif; LATS, large as mammalian Hippo signalling hereafter. Significantly,
tumour-suppressor; MOB, Mps one binder; hMOB, human MOB; MST, mammalian Ste20-like Drosophila geneticists not only provided an excellent name
serine/threonine; NDR, nuclear Dbf2-related; NTR, N-terminal regulatory domain; PPI, protein–
protein interaction; SARAH, Salvador/RASSF1A/Hippo.
for this novel signal transduction cascade, but also were
1
To whom correspondence should be addressed (email a.hergovich@ucl.ac.uk). the first to demonstrate that several components of Hippo
C The Authors Journal compilation
C 2012 Biochemical Society Biochem. Soc. Trans. (2012) 40, 124–128; doi:10.1042/BST20110619Signalling 2011: a Biochemical Society Centenary Celebration 125
signalling are actually tumour-suppressor proteins. For by MST1/2 [25,28]. The association of Salvador/WW45 with
example, loss of Hippo, Warts or Mats (the counterparts of MST1/2 through their SARAH domains has been shown
human MST1/2, LATS1/2 and MOB1 respectively) resulted to be essential for the terminal differentiation of epithelial
in uncontrolled tissue overgrowth in Drosophila [14–16]. cells [29]. Of note, RASSF1A and Salvador can also form
Even more importantly, loss of Hippo, Warts or Mats could a complex which seems to function independently of their
be functionally compensated by mammalian MST2, LATS1 interaction with MST1/2 [30]. Significantly, MST1/2 kinases
and MOB1A respectively [17–19]. Studies of transgenic mice can also function without their SARAH domains. On one
also showed that loss of MST1/2 or LATS1 results in the hand, caspase-cleaved MST1/2, which is hyperactive in spite
development of cancers [7,20–22]. Together, these studies of the deletion of the SARAH domains, is the predominantly
strongly suggest that the core components of mammalian expressed form in hepatocytes [22]. On the other hand, the
Hippo signalling represent tumour-suppressor proteins. Last, phosphorylation and activation of NDR kinase by MST1
but not least, one must also mention that Drosophila genetics in S-phase does not require the presence of a SARAH
also provided leads in how Hippo signalling can be regulated domain in MST1 [24]. Furthermore, MST3 kinase, which
by PPIs [9]. In the present paper, I give a brief overview of does not contain a SARAH domain, plays a major role in the
our current understanding of the importance and complexity phosphorylation and activation of NDR during G1 /S cell-
of these PPIs in mammalian Hippo signalling. cycle progression [31].
In conclusion, MST1/2 kinase activities are influenced
by signalling components containing SARAH domains.
PPIs in mammalian Hippo signalling: an RASSF1A and Salvador can activate MST1/2 by forming
overview SARAH domain-dependent complexes, suggesting that
Over the last few years, research in Drosophila and the SARAH domains of MST1/2 are required for
mammalian cell systems has demonstrated that Hippo kinase MST1/2 function in certain biological settings. Nevertheless,
signalling can be regulated on different levels by PPIs. RASSF1A and Salvador also seem to have MST1/2-
Intriguingly, the vast majority of these PPIs are mediated independent roles that potentially do not involve SARAH-
by three types of modular protein domains: (i) SARAH dependent signalling. In this context, it is also important
(Salvador/RASSF1A/Hippo) domains that are important for to mention that MST1/2 kinases can function completely
Hippo/MST activation; (ii) WW domains that can interact independently of their SARAH domains in some biological
with PPXY (Pro-Pro-Xaa-Tyr) motifs; and (iii) conserved settings. These observations illustrate that we have not yet
stretches of hydrophobic and basic residues in LATS/NDR fully understood how MST1/2 kinases can be regulated
kinases [also termed NTRs (N-terminal regulatory domains)] independently of and dependently on PPIs. The identification
that mediate the binding of LATS/NDR to MOB proteins. of conserved SARAH domains has been very helpful in
Hippo signalling can also be controlled by other types of defining how RASSF1A and Salvador can activate the
PPIs [6,9–11]. However, given that these three subgroups of core cassette of mammalian Hippo signalling, but recent
PPIs clearly represent the best studied PPIs in mammalian evidence suggests that various MST1/2 signalling events
Hippo signalling, I focus my discussion on the functionality should be re-addressed with regard to their dependency on
of SARAH, WW and NTR domains in mammalian Hippo SARAH domains, and possibly also other motifs such as the
signalling. PPXF (Pro-Pro-Xaa-Phe) motifs in MST1/2. In our opinion
SARAH-independent protein domains of MST1/2 need to
Hippo signalling and SARAH domain-containing be studied in more detail, since we cannot currently exclude
proteins the possibility that MST1/2 are regulated by PPIs that are
As already mentioned, members of the MST kinase family completely independent of these SARAH domains.
phosphorylate and thereby activate LATS/NDR kinases
[5]. In particular, the MST1 and MST2 kinases play an Hippo signalling and WW domain-containing
important role in the activation of LATS/NDR kinases [22– factors
25]. Intriguingly, MST1/2 contain a C-terminal domain that Since Sudol and Harvey [9] recently summarized the
is not present in the other three MST kinase family members importance of the WW module in Hippo signalling, I provide
[5,26]. Since this C-terminal domain was also found in only a brief overview on WW domains. Nevertheless, I
Salvador/WW45 and RASSF1A, two regulators of MST1/2 will take the time to highlight very recent progress in our
activity [26], this domain was termed the SARAH domain for understanding of WW domain-dependent Hippo signalling.
Salvador/RASSF1A/Hippo [27]. Current evidence suggests The WW domain is a small modular protein domain of
that the SARAH domain of MST1/2 is required for their approximately 40 amino acids in length, which contains two
auto-phosphorylation activity, plays a key role in the PPI highly conserved tryptophan (W) residues [32]. The majority
of MST1/2 with the tumour-suppressor protein RASSF1A, of WW domains recognize short PPXY motifs, and the
and is required for the interaction of MST1/2 with the phosphorylation of tyrosine (Y) in these PPXY motifs has
scaffolding protein Salvador/WW45 [26]. The interaction of been shown to block WW–PPXY interactions. Considering
MST1/2 with RASSF1A through their SARAH domains that several Hippo signalling components contain either WW
appears to regulate the activation of LATS/NDR kinases domains or PPXY motifs [9], WW–PPXY-mediated PPIs
C The Authors Journal compilation
C 2012 Biochemical Society126 Biochemical Society Transactions (2012) Volume 40, part 1
have been studied the most extensively among all known PPIs NDR1/2 on the hydrophobic motif (HM phosphorylation)
currently known to play a role in Hippo signalling. LATS1/2 by MST kinases [12]. In contrast, binding of hMOB1 to
kinases regulate the proto-oncogene YAP through WW– LATS1/2 kinases seems to be only required for T-loop phos-
PPXY-mediated interactions [33,34], where the LATS–YAP phorylation, whereas HM phosphorylation is independent
interaction seems to serve two purposes: (i) phosphorylation of hMOB1–LATS complex formation [46]. This illustrates
of YAP by LATS1/2 results in the inactivation of YAP by that hMOB1–NDR and hMOB1–LATS complexes are not
creating a 14-3-3-anchor site and changing the subcellular equal, thereby allowing cells to trigger different biological
localization of YAP [33,35–37]; and (ii) the direct protein– outputs through hMOB1 signalling [12]. Of importance,
protein complex formation between LATS1/2 and YAP can the regulation of LATS/NDR kinases by hMOB1 is even
further negatively affect YAP activity [33,34]. Significantly, more complicated. hMOB1 is phosphorylated on Thr12
AMOTL (angiomotin-like protein) 1 and 2 can also bind and Thr35 by MST1 and MST2, which results in increased
to the YAP WW domain with their PPXY motifs [38–40]. affinity of phospho-hMOB1 for NDR/LATS kinases [46].
Similarly to LATS1/2, AMOTL1/2 negatively regulate the This increased formation of hMOB1–NDR and hMOB1–
nuclear activity of YAP by altering the subcellular localization LATS complexes results in increased phosphorylation of
of YAP. Furthermore, Camargo and colleagues showed LATS/NDR kinases. Therefore hMOB1-regulated signalling
recently that the activity of YAP is negatively controlled by through binding to LATS/NDR can be regulated by MST
α-catenin binding in keratinocytes [41]. More specifically, kinase activity.
they provided evidence suggesting that the binding of α- Another level of complexity between hMOB1–NDR and
catenin to the YAP WW domain can maintain YAP in its hMOB1–LATS complexes is how they can be influenced
phosphorylated inactive state, whereas MST/LATS signalling by hMOB2. In spite of the highly conserved hMOB1-
was dispensable for efficient YAP regulation in this setting binding domain shared between NDR and LATS kinases
[41]. Last, but not least, one should also note that the WW [47,48], hMOB2 interacts with NDR1/2 kinases through
domain-containing protein Kibra interacts with LATS1/2 the hMOB1-binding domain, but does not associate with
[42–44]. The association of the PPXY motif of LATS1/2 with LATS1/2 kinases [49]. Significantly, binding of hMOB2
the WW domains of Kibra appears to play a role in the to NDR1/2 kinases inhibits the phosphorylation of NDR
activation of LATS1/2 kinases [45], but the precise mechanism and thereby blocks kinase activation [49]. This inhibition
is not yet well understood, since the activation of LATS1/2 is most likely to be caused by competition between
by Kibra seems to be MST1/2-independent [45]. hMOB1 and hMOB2 for direct binding to the same domain
Taken together, PPIs of WW domains with PPXY motifs within NDR1/2 kinases, since a hMOB2 mutant deficient
are a common feature of mammalian Hippo signalling. Using in NDR1/2 binding could not interfere with the activation of
WW–PPXY interactions, the nuclear activity of the proto- NDR by hMOB1 [49].
oncogene YAP can be influenced by direct binding of YAP Taken together, the PPI of hMOB1 with LATS/NDR
to LATS1/2, AMOTL1/2 and α-catenin. Given the wide kinases is crucial for the phosphorylation and activation
occurrence of WW domains and PPXY motifs in all of these of LATS/NDR kinases. The efficiency of hMOB1 binding
Hippo signalling components, we fully agree with Sudol and to LATS/NDR kinases can be influenced by MST1/2-
Harvey [9] that it is very likely that more factors playing a mediated phosphorylation of hMOB1. A second human
role in mammalian Hippo signalling will be identified in the MOB protein, hMOB2, also plays a role in the regulation
near future based on sequence comparison approaches. of NDR/LATS kinase signalling, more specifically in the
inhibition of NDR signalling. Therefore hMOB2 has been
Regulation of Hippo signalling by MOB proteins classified as an inhibitor of NDR signalling, whereas hMOB1
As mentioned above, PPIs also play a role in the regulation has been classified as a co-activator of NDR/LATS signalling
of LATS/NDR kinase activities. In addition to the binding of cascades.
LATS1/2 to Kibra [45], members of the highly conserved
family of MOB co-activator proteins can associate with
LATS/NDR kinases. More specifically, hMOB1 (human Conclusions
MOB1) can bind to all four human LATS/NDR kinases In summary, mammalian Hippo signalling is controlled
[12]. Combined structural and biochemical studies have by various PPIs that can influence the activities of MST
shown that a stretch of conserved hydrophobic and positively and LATS/NDR kinases, as well as alter the subcellu-
charged residues N-terminal to the catalytic domains lar localizations of the proto-oncogenes YAP and TAZ
of LATS/NDR kinases is required for the association of (Figure 1). Currently, we are aware of three main types of
hMOB1 with LATS/NDR kinases, whereas a conserved modular protein domains that are repeatedly utilized for
cluster of negatively charged residues on hMOB1 is needed PPIs regulating Hippo signalling. First, SARAH domains
for the interaction of hMOB1 with LATS/NDR kinases are important for the activation of MST1/2 kinases by the
[12]. The binding of hMOB1 to NDR1/2 kinases through tumour-suppressor proteins RASSF1A and Salvador/WW45.
these conserved domains triggers auto-phosphorylation of Secondly, the WW domain-containing proteins Kibra,
NDR1/2 on the activation segment (also known as T-loop YAP and TAZ can bind to PPXY motifs in LATS1/2
phosphorylation), and also facilitates the phosphorylation of kinases and AMOTL1/2 respectively. Thirdly, the association
C The Authors Journal compilation
C 2012 Biochemical SocietySignalling 2011: a Biochemical Society Centenary Celebration 127
Figure 1 The complexity of selected PPIs in mammalian Hippo WW domains and one C-terminal SARAH domain, whereas
signalling LATS kinases contain one NTR domain and at least one
MST1/2 kinases are activated by binding to RASSF1A and Salvador PPXY motif. Definitely different binding partners should
through conserved SARAH domains. MST1/2 associate with and be addressed in parallel, in order to allow comprehensive
activate LATS/NDR kinases by phosphorylation. LATS/NDR activities are snapshots of a range of PPIs. Taken together, this would
controlled by binding to hMOB1/2 proteins using the NTR domains suggest the need to study as many PPIs as possible when
of LATS/NDR. Kibra also influences LATS activity through a WW–PPXY analysing mammalian Hippo signalling. In particular, novel
interaction. LATS associates with YAP and TAZ using WW–PPXY domains, functions of YAP signalling (such as the role in stem cell
which play a role in the inhibition of YAP and TAZ. AMOTL1/2 renewal [50]) and its regulation by PPIs will be of utmost
proteins further negatively regulate YAP and TAZ activities through importance.
WW–PPXY-mediated PPIs.
Acknowledgements
I thank D. Cook, L. Hoa and J. Lisztwan for their critical input on this
paper. I apologize to all of my colleagues whose excellent work
could not be cited owing to space limitations
Funding
This work was supported by the Wellcome Trust [grant number
090090/Z/09/Z]. A.H. is a Wellcome Trust Research Career
Development Fellow at the UCL Cancer Institute.
References
1 Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of cancer: the next
generation. Cell 144, 646–674
of LATS/NDR kinases with MOB1/2 proteins stimulates 2 Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S.
or inhibits kinase activation. The latter PPI is influenced (2002) The protein kinase complement of the human genome. Science
by MST1/2 kinase activities. hMOB1 phosphorylated by 298, 1912–1934
3 Pearce, L.R., Komander, D. and Alessi, D.R. (2010) The nuts and bolts of
MST1/2 binds more readily to LATS/NDR kinases, thereby AGC protein kinases. Nat. Rev. Mol. Cell Biol. 11, 9–22
leading to increased LATS/NDR phosphorylation and 4 Hergovich, A., Cornils, H. and Hemmings, B.A. (2008) Mammalian NDR
activation. The tyrosine residue in the PPXY motif might protein kinases: from regulation to a role in centrosome duplication.
Biochim. Biophys. Acta 1784, 3–15
also be a target of tyrosine protein kinases, which could 5 Hergovich, A., Stegert, M.R., Schmitz, D. and Hemmings, B.A. (2006)
significantly affect formation of Kibra–LATS, YAP–LATS, NDR kinases regulate essential cell processes from yeast to humans.
TAZ–LATS, AMOTL–YAP and AMOTL–TAZ complexes. Nat. Rev. Mol. Cell Biol. 7, 253–264
6 Badouel, C. and McNeill, H. (2011) SnapShot: the Hippo signaling
Last, but not least, it is also possible that the phosphorylation pathway. Cell 145, 484
of the SARAH domain could influence the formation of 7 Hergovich, A. and Hemmings, B.A. (2009) Mammalian NDR/LATS protein
RASSF1A–MST and Salvador–MST complexes. However, kinases in hippo tumor suppressor signaling. Biofactors 35, 338–345
8 Pan, D. (2010) The hippo signaling pathway in development and cancer.
according to our knowledge, the regulation of the PPXY
Dev. Cell 19, 491–505
motif or the SARAH domain by phosphorylation has not 9 Sudol, M. and Harvey, K.F. (2010) Modularity in the Hippo signaling
yet been reported in mammalian Hippo signalling. pathway. Trends Biochem. Sci. 35, 627–633
Mammalian Hippo signalling plays crucial roles in various 10 Zhao, B., Li, L. and Guan, K.L. (2010) Hippo signaling at a glance. J. Cell
Sci. 123, 4001–4006
cellular processes. To a certain degree, the importance of 11 Zhao, B., Li, L., Lei, Q. and Guan, K.L. (2010) The Hippo–YAP pathway in
selected PPIs has already been addressed. For example, the organ size control and tumorigenesis: an updated version. Genes Dev.
modification of hMOB1 by MST1/2, which influences 24, 862–874
12 Hergovich, A. (2011) MOB control: Reviewing a conserved family of
the formation of hMOB1–LATS and hMOB1–NDR com- kinase regulators. Cell. Signalling 23, 1433–1440
plexes, has been studied in cell proliferation [46], apoptosis 13 Cornils, H., Kohler, R.S., Hergovich, A. and Hemmings, B.A. (2011)
signalling [22] and the control of the proto-oncogene YAP Downstream of human NDR kinases: Impacting on c-myc and p21
protein stability to control cell cycle progression. Cell Cycle 10,
[22]. Nevertheless, in spite of such progress, we feel that the
1897–1904
scientific community has only just started to study the role 14 Harvey, K. and Tapon, N. (2007) The Salvador–Warts–Hippo pathway: an
of PPIs in Hippo signalling in more detail. In particular, the emerging tumour-suppressor network. Nat. Rev. Cancer 7, 182–191
binding patterns of Hippo signalling components containing 15 Pan, D. (2007) Hippo signaling in organ size control. Genes Dev. 21,
886–897
more than one modular protein domain are not completely 16 Saucedo, L.J. and Edgar, B.A. (2007) Filling out the Hippo pathway. Nat.
understood. For example, Salvador/WW45 contains two Rev. Mol. Cell Biol. 8, 613–621
C The Authors Journal compilation
C 2012 Biochemical Society128 Biochemical Society Transactions (2012) Volume 40, part 1
17 Lai, Z.C., Wei, X., Shimizu, T., Ramos, E., Rohrbaugh, M., Nikolaidis, N., Ho, 35 Dong, J., Feldmann, G., Huang, J., Wu, S., Zhang, N., Comerford, S.A.,
L.L. and Li, Y. (2005) Control of cell proliferation and apoptosis by Mob as Gayyed, M.F., Anders, R.A., Maitra, A. and Pan, D. (2007) Elucidation of a
tumor suppressor, Mats. Cell 120, 675–685 universal size-control mechanism in Drosophila and mammals. Cell 130,
18 Tao, W., Zhang, S., Turenchalk, G.S., Stewart, R.A., St John, M.A., Chen, W. 1120–1133
and Xu, T. (1999) Human homologue of the Drosophila melanogaster 36 Huang, J., Wu, S., Barrera, J., Matthews, K. and Pan, D. (2005) The Hippo
lats tumour suppressor modulates CDC2 activity. Nat. Genet. 21, 177–181 signaling pathway coordinately regulates cell proliferation and apoptosis
19 Wu, S., Huang, J., Dong, J. and Pan, D. (2003) hippo encodes a Ste-20 by inactivating Yorkie, the Drosophila homolog of YAP. Cell 122, 421–434
family protein kinase that restricts cell proliferation and promotes 37 Zhao, B., Wei, X., Li, W., Udan, R.S., Yang, Q., Kim, J., Xie, J., Ikenoue, T.,
apoptosis in conjunction with salvador and warts. Cell 114, 445–456 Yu, J., Li, L. et al. (2007) Inactivation of YAP oncoprotein by the Hippo
20 Lu, L., Li, Y., Kim, S.M., Bossuyt, W., Liu, P., Qiu, Q., Wang, Y., Halder, G., pathway is involved in cell contact inhibition and tissue growth control.
Finegold, M.J., Lee, J.S. et al. (2010) Hippo signaling is a potent in vivo Genes Dev. 21, 2747–2761
growth and tumor suppressor pathway in the mammalian liver. Proc. 38 Chan, S.W., Lim, C.J., Chong, Y.F., Pobbati, A.V., Huang, C. and Hong, W.
Natl. Acad. Sci. U.S.A. 107, 1437–1442 (2011) Hippo pathway-independent restriction of TAZ and YAP by
21 Song, H., Mak, K.K., Topol, L., Yun, K., Hu, J., Garrett, L., Chen, Y., Park, O., angiomotin. J. Biol. Chem. 286, 7018–7026
Chang, J., Simpson, R.M. et al. (2010) Mammalian Mst1 and Mst2 39 Wang, W., Huang, J. and Chen, J. (2011) Angiomotin-like proteins
kinases play essential roles in organ size control and tumor suppression. associate with and negatively regulate YAP1. J. Biol. Chem. 286,
Proc. Natl. Acad. Sci. U.S.A. 107, 1431–1436 4364–4370
22 Zhou, D., Conrad, C., Xia, F., Park, J.S., Payer, B., Yin, Y., Lauwers, G.Y., 40 Zhao, B., Li, L., Lu, Q., Wang, L.H., Liu, C.Y., Lei, Q. and Guan, K.L. (2011)
Thasler, W., Lee, J.T., Avruch, J. et al. (2009) Mst1 and Mst2 maintain Angiomotin is a novel Hippo pathway component that inhibits YAP
hepatocyte quiescence and suppress hepatocellular carcinoma oncoprotein. Genes Dev. 25, 51–63
development through inactivation of the Yap1 oncogene. Cancer Cell 16, 41 Schlegelmilch, K., Mohseni, M., Kirak, O., Pruszak, J., Rodriguez, J.R., Zhou,
425–438 D., Kreger, B.T., Vasioukhin, V., Avruch, J., Brummelkamp, T.R. et al.
23 Chan, E.H., Nousiainen, M., Chalamalasetty, R.B., Schafer, A., Nigg, E.A. (2011) Yap1 acts downstream of α-catenin to control epidermal
and Sillje, H.H. (2005) The Ste20-like kinase Mst2 activates the human proliferation. Cell 144, 782–795
large tumor suppressor kinase Lats1. Oncogene 24, 2076–2086 42 Baumgartner, R., Poernbacher, I., Buser, N., Hafen, E. and Stocker, H.
24 Hergovich, A., Kohler, R.S., Schmitz, D., Vichalkovski, A., Cornils, H. and (2010) The WW domain protein Kibra acts upstream of Hippo in
Hemmings, B.A. (2009) The MST1 and hMOB1 tumor suppressors control Drosophila. Dev. Cell 18, 309–316
human centrosome duplication by regulating NDR kinase 43 Genevet, A., Wehr, M.C., Brain, R., Thompson, B.J. and Tapon, N. (2010)
phosphorylation. Curr. Biol. 19, 1692–1702 Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev.
25 Vichalkovski, A., Gresko, E., Cornils, H., Hergovich, A., Schmitz, D. and Cell 18, 300–308
Hemmings, B.A. (2008) NDR kinase is activated by RASSF1A/MST1 in 44 Yu, J., Zheng, Y., Dong, J., Klusza, S., Deng, W.M. and Pan, D. (2010) Kibra
response to Fas receptor stimulation and promotes apoptosis. Curr. Biol. functions as a tumor suppressor protein that regulates Hippo signaling in
18, 1889–1895 conjunction with Merlin and Expanded. Dev. Cell 18, 288–299
26 Ling, P., Lu, T.J., Yuan, C.J. and Lai, M.D. (2008) Biosignaling of 45 Xiao, L., Chen, Y., Ji, M. and Dong, J. (2011) KIBRA regulates Hippo
mammalian Ste20-related kinases. Cell. Signalling 20, 1237–1247 signaling activity via interactions with large tumor suppressor kinases. J.
27 Scheel, H. and Hofmann, K. (2003) A novel interaction motif, SARAH, Biol. Chem. 286, 7788–7796
connects three classes of tumor suppressor. Curr. Biol. 13, R899–R900 46 Praskova, M., Xia, F. and Avruch, J. (2008) MOBKL1A/MOBKL1B
28 Guo, C., Tommasi, S., Liu, L., Yee, J.K., Dammann, R. and Pfeifer, G.P. phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr. Biol.
(2007) RASSF1A is part of a complex similar to the Drosophila 18, 311–321
Hippo/Salvador/Lats tumor-suppressor network. Curr. Biol. 17, 700–705 47 Bichsel, S.J., Tamaskovic, R., Stegert, M.R. and Hemmings, B.A. (2004)
29 Lee, J.H., Kim, T.S., Yang, T.H., Koo, B.K., Oh, S.P., Lee, K.P., Oh, H.J., Lee, Mechanism of activation of NDR (nuclear Dbf2-related) protein kinase by
S.H., Kong, Y.Y., Kim, J.M. et al. (2008) A crucial role of WW45 in the hMOB1 protein. J. Biol. Chem. 279, 35228–35235
developing epithelial tissues in the mouse. EMBO J. 27, 1231–1242 48 Hergovich, A., Schmitz, D. and Hemmings, B.A. (2006) The human
30 Donninger, H., Allen, N., Henson, A., Pogue, J., Williams, A., Gordon, L., tumour suppressor LATS1 is activated by human MOB1 at the
Kassler, S., Dunwell, T., Latif, F. and Clark, G.J. (2011) Salvador protein is membrane. Biochem. Biophys. Res. Commun. 345, 50–58
a tumor suppressor effector of RASSF1A with Hippo 49 Kohler, R.S., Schmitz, D., Cornils, H., Hemmings, B.A. and Hergovich, A.
pathway-independent functions. J. Biol. Chem. 286, 18483–18491 (2010) Differential NDR/LATS interactions with the human MOB family
31 Cornils, H., Kohler, R.S., Hergovich, A. and Hemmings, B.A. (2011) reveal a negative role for human MOB2 in the regulation of human NDR
Human NDR kinases control G1 /S cell cycle transition by directly kinases. Mol. Cell. Biol. 30, 4507–4520
regulating p21 stability. Mol. Cell. Biol. 31, 1382–1395 50 Lian, I., Kim, J., Okazawa, H., Zhao, J., Zhao, B., Yu, J., Chinnaiyan, A.,
32 Bork, P. and Sudol, M. (1994) The WW domain: a signalling site in Israel, M.A., Goldstein, L.S., Abujarour, R. et al. (2010) The role of YAP
dystrophin? Trends Biochem. Sci. 19, 531–533 transcription coactivator in regulating stem cell self-renewal and
33 Hao, Y., Chun, A., Cheung, K., Rashidi, B. and Yang, X. (2008) Tumor differentiation. Genes Dev. 24, 1106–1118
suppressor LATS1 is a negative regulator of oncogene YAP. J. Biol. Chem.
283, 5496–5509
34 Oka, T., Mazack, V. and Sudol, M. (2008) Mst2 and Lats kinases regulate
apoptotic function of Yes kinase-associated protein (YAP). J. Biol. Chem. Received 8 June 2011
283, 27534–27546 doi:10.1042/BST20110619
C The Authors Journal compilation
C 2012 Biochemical SocietyYou can also read
