|
 Pdf file on The molecular mechanisms that underlie the tumor
suppressor function of LKB1
Dahua Fan, Chao Ma, and Haitao Zhang*
Affiliation: Department of Biochemistry and
Molecular Biology,
*Corresponding author: Tel, 86-759-2388581; Fax,
86-759-2388994; E-mail, [email protected]
Abstract
Germline mutations of the LKB1 tumor suppressor gene result in Peutz-Jeghers syndrome
characterized by intestinal hamartomas and increased incidence of epithelial
cancers. Inactivating mutations in LKB1
have also been found in certain sporadic human cancers and with particularly
high frequency in lung cancer. LKB1 has now been demonstrated to play a crucial
role in pulmonary tumorigenesis, controlling initiation, differentiation and
metastasis. Recent evidences showed that LKB1 is a multitasking kinase, with
great potential in orchestrating cell activity. Thus far, LKB1 has been found
to play a role in cell polarity, energy metabolism, apoptosis, cell cycle
arrest and cell proliferation, all of which may require the tumor suppressor
function of this kinase and/or its catalytic activity. This review focuses on
remarkable recent findings concerning the molecular mechanism by which the LKB1
protein kinase operates as a tumor suppressor and discusses the rational
treatment strategies to individuals suffering from Peutz-Jeghers syndrome and
other common disorders related to LKB1 signaling.
Keywords LKB1; tumor suppressor;
Peutz-Jeghers syndrome; lung adenocarcinoma
Received: September 01, 2008 Accepted: October 23, 2008
Introduction
The LKB1 gene was discovered only in 1998 as
a new tumor suppressor gene by linkage analysis of Peutz-Jeghers syndrome (PJS)
[1,2]. PJS is a rare autosomal-dominant polyposis disorder that was first
described in a Dutch family by Peutz in 1921 [3], and later by Jeghers et al. in 1949 [4]. The disease is
characterized by the presence of hamartomatous polyps in the gastrointestinal tract
and by melanin spots on the lips, buccal mucosa and digits [3,4].
Gastrointestinal tumors are the most commonly diagnosed malignancies in PJS
patients, but the risk of developing cancer from other origins including
breast, intestine, testis, cervix and pancreas, are also significantly high [5–10]. In 1998, groundbreaking genetic linkage analysis undertaken by
two independent groups revealed that germline mutations of the LKB1 gene, which is located on
chromosome 19pl3.3 are the cause of the majority of PJS cases [1,2]. In most
previous studies, LKB1 mutations
proved to be detectable in 35–70% of PJS patients [11–13]. However, in these studies, screening methodologies for
identifying LKB1 mutations in PJS
were mostly limited to detect point mutations and small scale intra-exonic
deletions/insertions. It was supposed that the prevalence of LKB1 mutations in PJS were
underestimated in these reports. The recently developed multiplex
ligation-dependent probe amplification assay for PJS allows a systematic search
for large deletions in the LKB1 gene.
Using this technique, three research groups found whole gene or exon deletions
of LKB1 account for 39% [14], 32%
[15] and 50% [16] of the patients in whom no point mutation had been detected,
or 14%, 16% and 24% of all patients examined, respectively. According to these
studies, the total percentage of LKB1
inactivation in PJS patients ranged from 66% to 94% [14–16]. Consistent with this finding, de Leng and colleagues have
recently found that 91% of the studied families showed LKB1 inactivation, which included 78% point mutations and 13% exon
deletions or even whole gene deletions [17].
Beside
that germline mutations of the LKB1
gene are responsible for PJS, genetic alterations of LKB1 have also been found to play a causal role in certain sporadic
human cancers [18], especially in lung cancer [19–21]. Remarkably, most of the observed cancers are associated with
somatic sequence mutations accompanied by loss of heterozygosity of the LKB1 gene, which lead to the generation
of truncated and, therefore, inactive LKB1 proteins [22,23]. What is more, the
truncated transcript of LKB1 is
significantly down-regulated and the truncated LKB1 protein is virtually
undetectable in certain of sporadic cancer cell lines [23–25]. Promoter methylation accounts for a small fraction of repressed
LKB1 expression cases [24, 25], but
this is unlikely a major contributing mechanism in non-small cell lung
carcinoma cell lines [23]. Additionally, homozygous deletions of LKB1 have been observed in sporadic
pancreatic and biliary adenocarcinomas [26]. It is suggested that biallelic
inactivation of LKB1 could favor
progression to malignancy [22]. Although somatic LKB1 alterations are rare in sporadic cancers, there are at least
one-third sporadic lung adenocarcinoma harbor somatic mutations at the LKB1 gene [19–21]. More recently, Ji et al.
have demonstrated that LKB1 plays a crucial role in pulmonary tumorigenesis,
controlling initiation, differentiation and metastasis [6]. It is evident from
the recent reports that LKB1 is a master kinase that can potentially activate
several downstream kinases by phosphorylating a conserved threonine in their
activation loops [27], among which partitioning defective gene 1 (Par-1)/microtubule
affinity-regulating kinases (MARKs) and AMP-activated protein kinase (AMPK) are
two kinases that have been extensively characterized [28–33]. LKB1 can also phosphorylate and activate 13 protein kinases
from the AMP-activated protein kinase family [27]. Therefore, LKB1 is a
multitasking kinase, with great potential in orchestrating cell activity. The
pathogenic mechanism of LKB
Characteristics of the LKB1 Gene and Encoded
Protein
The LKB1 gene (also known as serine/threonine kinase 11, STK11), maps to the chromosomal region
19p13.3, is the first serine/threonine kinase gene whose inactivating germline
mutations cause a cancer susceptibility syndrome [33]. It spans 23 kb and is
made up of nine coding exons and a final noncoding exon [1]. LKB1 encodes for an mRNA of ~2.4 kb
transcribed in telomere-to-centromere direction and for a protein of 433 amino
acids and approximately 48 kDa [1]. The protein, which has serine-threonine
kinase activity, possesses a nuclear localization signal in the N-terminal
noncatalytic region (residues 38–43) and a
kinase domain (residues 49–309)
[38]. The N-terminal and C-terminal noncatalytic regions of LKB1 are not
related to any other proteins and possess no identifiable functional domains
[1,2]. LKB1 has now been classified as a member of the calcium/calmodulin regulated
kinase-like family that is part of the Ca2+/calmodulin kinase group
of kinases (http:// www.kinase.com).
Human
LKB1 shows strong homology to the cytoplasmic serine/threonine kinases of
several organisms, including Xenopus
laevis egg and embryonic kinase 1 (XEEK1), mouse LKB1, Caenorhabditis elegans partitioning defective gene 4 (Par-4), and
drosophila LKB1 [39–42].
There is
a 92.5% similarity between mouse and human LKB1
genes, and 97.5% in their core kinase domain. Similarly, there is 84.5% and 96.2%
similarity between the core kinase domains of LKB1 of mouse and xenopus,
respectively [43,44].
LKB1 is
expressed ubiquitously in adult and fetal tissues, especially in pancreas,
liver, testes and skeletal muscle [45–49]. LKB1
signaling is regulated through two main mechanisms: phosphorylation and
subcellular localization. LKB1 can be phosphorylated on at least 8 residues [50–57], and its phosphorylation is thought to play a key role in cell
cycle arrest, tumor suppression, and cell polarity [38].
In vivo, LKB1 forms a
heterotrimeric complex with two proteins termed STE20-related adaptor (STRAD)
and mouse protein 25 (MO25), which play a crucial role in regulating LKB1
protein stability, kinase activity and cellular localization [58–60]. Although STRAD possesses STE20-like kinase domain, it has been
classified as a pseudokinase because it lacks key residues present in other
kinases that are required for catalysis [58]. The binding of STRAD to LKB1
substantially activates the autophosphorylation of LKB1 and hence its ability
to phosphorylate downstream substrates. STRAD could also direct the subcellular
localization of LKB1 by anchoring it in the cytoplasm [58]. MO25 is a
scaffolding protein of 40 kDa that stabilizes the binding of STRAD to LKB1,
stimulating the catalytic activity of LKB1 approximately 10-fold [59]. The
crystal structure of full-length MOof STRADa with LKB1 by generating additional binding site(s) on STRADa [59,61]. Dorfman et al.
have recently provided a model of the mechanism that determined the
nucleocytoplasmic transport of the LKB1 protein kinase [62]. It is demonstrated
that STRADa is indispensable for the cytoplasmic
localization of LKB1 as there is no nuclear export signal in LKB1. In the
nucleus, STRADa acts as an adaptor capable of
conjoining LKB1 to exportins CRM1 and exportin7, facilitating nuclear export of
LKB1. While in the cytoplasm, STRADa serves
as a competitor to importin-a/b for binding to LKB1, inhibiting reimport of LKB1. There is no
evidence of MO25 directly facilitating the nucleocytoplasmic shuttling of LKB1-
STRADa complex. The function of MO25 seems to
be limited to enhance the affinity of STRADa for LKB1 [62]. It has been demonstrated that the activities of many
signaling proteins associated with cancer are regulated by nucleocytoplasmic
shuttling [63,64]. It is plausible that translocation between various cellular
compartments allows for an additional level of spatial regulation of the LKB1
protein kinase activity.
Role of LKBNo
matter for constructing the cellular and whole body architecture or for
maintaining cellular and tissue function, the importance of establishing and
maintaining proper cell polarity can never be over emphasized in multicellular
organisms. Loss of cell polarity strongly correlates with more aggressive and
invasive growth of malignant cells in human cancers [65]. The role of LKBBaas et al. have provided the most convincing
evidence that LKB1 also regulates cell polarization in a mammalian system [34].
In a STRAD inducible system, activation of LKB1 has been found to reorganize
the actin cytoskeleton and to relocalize some junctional proteins, inducing the
formation of a brush border and gap junctions even in the absence of cell-cell
contacts [34]. Consistently, more recent studies have also suggested that
mammalian LKB1 helps to establish cell polarity [69,70]. Barnes et al. disrupted expression of LKBAt this
stage, the question mainly arises as to the nature of the LKBThe
brain-specific kinase 1 (BRSK1, also known as SAD-A) and BRSK2 (SAD-B) that are
activated by LKB1 are mainly expressed in the brain and in low levels in the
testis [75]. SAD-A (BRSK1) was originally identified as a novel
serine/threonine kinase in C. elegans
in 2001 [76]. Crump et al.
demonstrated that SAD-A (BRSK1) controlled several aspects of presynaptic
differentiation, such as presynaptic vesicle clustering and axon termination.
SAD-A loss-of-function mutants in C.
elegans display polarity defects in neurons [76]. Similarly, mice lacking
both the SAD-A and SAD-B kinases were reported to die at birth because of
failure of their neurons to polarize and form axons and dendrites, showing that
these kinases are required for neuronal polarity in mammals [75]. More
recently, Hung et al. have further
confirmed that SAD-A interact directly with Neurabin, a scaffolding protein,
regulating neuronal polarity in C.
elegans. They have proposed that Neurabin facilitates SAD-A to
phosphorylate substrates that are specific for synapse formation during
neuronal polarization [77]. Collectively, these results suggest that the BRSK
(SAD) kinases, activated by LKB1, may play a specific role in regulating
polarization of neuronal cells.
For a
long time, there was a hypothesis that LKB1 signaling mediated by AMPK has been
limited to its role in controlling cellular energy metabolism [78]. Quite
recently, however, two independent groups almost simultaneously demonstrated
that AMPK also plays a role in maintaining normal cellular architecture and
cell polarity [79,80]. Lee and co-workers generated the first ampk-null mutants in animal model,
surprisingly, to discover that AMPK is a critical downstream mediator of LKBBy
strongly reducing the availability of sugar in the culture medium, ampka mutant epithelial cells displayed a completely disrupted
apical-basal polarity, accompanied by a sharply reduced amount of basal stress
fibers and an increased amount of apical F-actin in ampka mutant follicle cells [80].
Additionally,
Lee et al. have also provided a
plausible answer to the question of how AMPK controls cell polarity. They have
proposed that the regulatory light chain of nonmuscle myosin II (MRLC, also
known as MLC2) is the physiological substrate of AMPK. It has been observed
that the expression of a constitutively active MRLC, whose regulatory
phosphorylation site was mutated into phosphomimetic glutamates, not only can
rescue the epithelial polarity defects caused by the loss of AMPK but also can
restore the epithelial polarity defects of lkb1-null wing imaginal discs [80].
These results provide a potential mechanism for LKB1 signals through AMPK to
coordinate epithelial polarity and proliferation with cellular energy status,
and this might underlie the tumor suppressor function of LKB1.
More
recently, a novel LKB1-Cdc42-PAK pathway has been proposed to regulate cell
polarity in non-small cell
lung cancer [81]. It has been demonstrated that Cdc42,
a small GTPase of the
Role of LKBThe
AMP-activated protein kinase (AMPK) is an evolutionally conserved Ser/Thr
kinase that functions as a key regulator of cellular energy metabolism [35,78].
AMPK is a heterotrimeric complex comprising a catalytic AMPKa subunit and regulatory AMPKb and AMPKg
subunits. The g-subunit has 4-cystathionine-b-synthase domains, which are required for the binding of AMP or ATP,
increasing or decreasing AMPK activity, respectively [35]. Binding of AMP to
the g-subunit is thought to stimulate
phosphorylation of ThrAs its
name suggests, AMPK is allosterically activated by 5¢-AMP, an effect antagonized by high concentrations of ATP. Because
of the reaction catalyzed by adenylate kinase (2ADP— ATP + AMP), the AMP:ATP
ratio varies approximately as the square of the ADP:ATP ratio, making the
former ratio (essentially the parameter to which AMPK responds) a sensitive
indicator of reduced cellular energy status [86,87]. Consequently, any cellular
or metabolic stress (such as glucose deprivation, hypoxia, oxidative stress,
hyperosmotic stress, tissue ischemia and muscle contraction/exercise) that either
inhibits ATP synthesis or that accelerates ATP consumption will cause AMPK
activation [87]. Once activated, AMPK “switches off” many anabolic pathways
while “switches on” catabolic pathways that serve to restore intracellular ATP
level [88].
Early
studies provided evidence that AMPK mediates glucose transport in skeletal
muscle. AICAR-induced activation of AMPK causes insulin-independent increases
in skeletal muscle glucose transport, suggesting that the activation of AMPK
can lead to the activation of glucose transport in skeletal muscle [89]. AMPK
has also been suggested to be a critical regulator of fatty acid oxidation by
phosphorylating and inactivating acetyl CoA carboxylase (ACC), which results in
decreased production of the carnitine palmitoyltransferase I (CPT1) inhibitor,
malonyl-CoA. CPT1 promotes fatty acid transport into mitochondria for
subsequent oxidation [90,91]. Furthermore, Koh et al. have found that muscle-specific LKB1 knockout mice have elevated intramuscular triglycerides [92].
Using a similar muscle-specific LKB1
knockout mouse model, Thompson et al.
have shown impaired AICAR-induced fatty acid oxidation [93]. Taken together,
LKB1-AMPK pathway plays a critical role in regulating glycolysis and fatty acid
oxidation to maintain cellular energy levels immediately through short-term
effect on phosphorylation of regulatory proteins.
In
addition, LKB1-AMPK pathway exerts more long-lasting effects to restore
intracellular energy level by targeting both transcription and translation to
inhibit cell growth and proliferation [94–96]. The inhibition of translation through cross-talk with the
TSC1/TSC2-mTOR signaling pathway is a typical example [97,98]. Recent studies
from several laboratories have demonstrated that LKB1 is necessary for mammalian target of rapamycin (mTOR) repression under low ATP conditions in an AMPK- and
TSC2-dependent manner [97,98]. When activated by LKB1 under energy stresses,
AMPK has been shown to phosphorylate and activate TSC2, which then suppresses
mTOR signaling towards the key translational regulators 4E-BP1 and S6K1 [97].
Consistent with these observations, LKB1-deficient mouse embryonic fibroblasts
and gastrointestinal polyps derived from LKB1
mutant mice have been found to exhibit elevated levels of S6K1 activity and
phosphorylation of 4E-BP1, indicating of an aberrantly elevated mTOR signaling.
Furthermore, reintroduction of wild-type LKB1 into HeLa cells restores
AICAR-dependent inhibition of S6K1 and 4E-BP1 phosphorylation in response to
ATP depletion, indicating that LKB1-dependent mTOR regulation is conserved in
different cell types [98]. In short, these studies provided an indication that
LKB1exerts its long-lasting effects in regulating metabolism partly through its
ability to regulate the mTOR pathway.
However,
it seems likely that additional LKB1 effectors intervening in metabolism also
should be characterized. As is discussed above, the Ser/Thr protein kinase
Par-1b/MARK2/Emk is part of a larger subfamily of kinases that includes 13
members, most of which appear to be regulated by LKB1 [27–29]. The Par-1b/MARK2 protein kinase is conserved from yeast to
human and has been shown in multiple organisms and cell types to be critical
for regulation of cellular polarity [34,68,71,72]. Surprisingly, recent studies
by Hurov et al. have suggested that
the polarity kinase Par-1b/MARK2/Emk is a novel regulator glucose metabolism in vivo [36]. It is the first study that
this kinase is implicated in metabolic functions akin to those previously
defined for AMPK. A series of remarkable metabolic disorders have been observed
in Par-1b null mice, including decreased adiposity, hypermetabolism, insulin
hypersensitivity, resistance to diet-induced obesity, and enhanced glucose
uptake into white and brown adipose tissue [36]. Taken together, the finding
that Par-1b plays a critical role in regulating glucose metabolism and energy
balance proposes the exciting possibility that this kinase may be a valuable
drug target for the treatment of type 2 diabetes and obesity.
LKBThe
polyp formation in PJS could be due to the increased cell proliferation or
decreased apoptosis, and/or the involvement of both pathways [99]. Several
studies have indicated that overexpression of wild type LKBIt has
been found that LKB1-mediated G1 arrest is overcome by co-expression of cyclin
D1 or cyclin E, which suggests that LKB1 signaling leads to a decrease in the
activity of endogenous G1 cyclin-dependent kinase (CDK)-cyclin complexes.
Further studies have demonstrated that forced LKB1 expression in G361 cells, a
melanoma cell line that lacks endogenous LKB1, enhances the expression of the
CDK inhibitor p21/WAF1 through activating its transcription from promoter.
Moreover, both LKB1-mediated induction of p21 and LKB1-mediated growth arrest
are proved to be p53-dependent [104]. Zeng et
al. have confirmed and extended previous observations by demonstrating that
LKB1 binds to and stabilizes pOn the
other hand, studies on the absence of apoptosis in PJS polyps reveal that LKB1
is an inducer of apoptosis in vivo [108–111]. Karuman et al. have
demonstrated firstly that LKB1 can induce apoptosis in epithelial cells and
that the kinase activity of LKB1 is required for the induction of apoptosis.
Furthermore, they have proposed that p53 and LKB1 can physically interact and
that the presence of functional p53 is critical in mediating LKB1-induced
apoptosis, as overexpression of LKB1 induced apoptosis mainly in cells with
functional p53. However, it has also been found that p53–/–
mice do not exhibit a defect in apoptosis of stem cells where LKB1 is clearly
activated in dying cells, which might indicate the existence of a LKB1-mediated
p53-independent apoptosis pathway [108]. Previous studies have suggested that
the c-Jun N-terminal kinase (JNK) is a member of MAPK family, activation of
which is required for the release of cytochrome c from the mitochondria and the
subsequent activation of the caspase-mediated apoptosis [109]. Using the
Drosophila model system, Lee et al.
have recently discovered a genetic connection between LKB1 and the JNK pathway
and have demonstrated that the JNK pathway acts as a downstream effector of
LKB1 by mediating the LKB1-induced apoptosis [110]. LKB1 activates JNK via the
Hep-dependent pathway, and this activation is one of the crucial functions of
endogenous LKB1 during embryonic neuronal development in Drosophila, whereas,
blockage of the JNK signaling pathway strongly suppresses the LKB1-induced
apoptosis. Surprisingly, the LKB1-induced apoptosis has been found to be
caspase dependent but p53 independent in the Drosophila model system, as it is
not suppressed at all by the dominant-negative p53, while completely suppressed
by Drosophila inhibitor of apoptosis (DIAP) [110]. Furthermore, it has also
been observed that LKB1 is dispensable for p53-dependent apoptosis in the DNA
damage-induced apoptotic signaling [111]. Therefore, it is interesting to find
that LKB1 and p53 keep each other at an arm’s length, as they work either in
collaboration or independently to mediate cell apoptosis responding to
different cell types and cell conditions.
Remarkably,
recent studies have suggested that LKB1 acts as either an inducer or suppressor
of apoptosis depending on the severity of energy stress and cell types
[85,112]. Contrary to the observations that LKB1 can mediate apoptosis under
normal energy conditions, Shaw et al.
have found that LKB1 is essential to protect cells from apoptosis under energy
stress, while, LKB1 deficient cells are hypersensitive to apoptosis in response
to elevated intracellular AMP. Moreover, LKB1-deficient cells are also
sensitized to death induced by the AMP analogue AICAR. Therefore, it is
suggested that LKB1-AMPK signaling plays a role in protecting cells from
apoptosis in response to agents that increase the cellular AMP/ATP ratio [85].
Consistent with this view, in more recent studies, Mukherjee et al. have demonstrated that energy
stress induced by glucose withdrawal or addition of 2-deoxyglucose causes more
ATP depletion, AMPK phosphorylation and apoptosis in LKB1 deficient mouse
astrocytoma cells than in syngeneic normal astrocytes [112]. Taken together, it
is hypothesized that active LKB1-AMPK signaling offers a protective effect by
allowing the cell time to attempt to reverse the aberrantly high ratio of
AMP/ATP. If unable to reverse this ratio, however, the cell eventually will
undergo apoptosis [85,112].
Conclusions and Perspectives
Ten years have now passed since LKB1 was identified as the causative
gene of PJS [1,2], remarkable progress has been made in the structural and
functional analysis of LKBAs discussed above, LKB1 does not
represent an ideal drug target itself because drugs that inhibited LKB1 might
be expected to induce tumors. However, the inhibition of LKB1 or AMPK pathway
might also be supposed to make cancer cells more sensitive to apoptosis and
thus make cells more resistant to cell transformation by conventional oncogenes
through reducing the ability of tumor cells to tolerate and survive low energy
conditions, such as hypoxic situations found in tumors or following
chemotherapy [38]. How on
earth does the LKB1-AMPK pathway act to suppress tumorigenesis or to rescue
cancer cells from metabolic collapse? A new breakthrough from the Alessi
laboratory has given a conclusive answer that the LKB1-AMPK pathway plays a
vital role in suppressing tumorigenesis in PTEN (phosphatase and tensin
homologue deleted on chromosome 10)-deficient mice [113]. It has been observed
that AMPK-activating drugs (metformin, phenformin and A769662), traditionally
used to counter the metabolic changes observed in diabetes, effectively
restrain cancer cell growth in PTEN+/– mice. Furthermore, they have also proposed that it
is inadvisable to pharmacologically inhibit LKB1 and/or AMPK, at least for
the treatment of cancers in which the mTORC1 pathway is activated.
Collectively, these results have demonstrated that the activation of AMPK by
AMPK-activating drugs, such as clinically approved metformin and phenformin, is
likely to be of significant therapeutic value in a wide spectrum of human tumors
[113]. In future work, it would be interesting to further explore the anticancer effects of metformin and the potential medical benefits offered by targeting the AMPK/mTOR signaling pathway. Further investigation is also required
to provide the details of LKB1 protein structure and its enzymatic kinetics to
define better how LKB1 activity modulates its downstream substrates. To obtain
high-level expression of LKB1, however, seems to be a major obstacle to study
its crystal structure and function in vitro. Liu et al. have recently
established a high-level expression system of active human LKB As mentioned above, loss-of-function mutations in LKB1 are particularly
common in human lung cancers [6]. In human lung cancer, loss of LKB1 is
frequently associated with gain-of-function mutations in Ras. Other challenges
for future research will be to understand why mutations of LKB1 are so prevalent in lung cancer and the role that Ras and/or carcinogens play in promoting
transformation of LKB1-deficient lung cells.
Funding
This work was supported by the grants from the key
subject Foundation of Guangdong Province and the
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