Dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5
We report here for the first time specific interaction between tuberous sclerosis complex 2 (TSC2) and protein phosphatase 5 (PP5) in mammalian cells. We found that the interaction is stronger in exponentially growing and serum stimulated cells when compared to serum starved cells. In addition, we p...
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Інститут молекулярної біології і генетики НАН України
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Malanchuk, O.M. Palchevskyy, S.S. Filonenko, V.V. 2019-06-20T17:40:13Z 2019-06-20T17:40:13Z 2008 Dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5 / O.M. Malanchuk, S.S. Palchevskyy, V.V. Filonenko // Біополімери і клітина. — 2008. — Т. 24, № 2. — С. 176-179. — Бібліогр.: 16 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00079F https://nasplib.isofts.kiev.ua/handle/123456789/157679 577.218; 616-006 We report here for the first time specific interaction between tuberous sclerosis complex 2 (TSC2) and protein phosphatase 5 (PP5) in mammalian cells. We found that the interaction is stronger in exponentially growing and serum stimulated cells when compared to serum starved cells. In addition, we provide the evidence that PP5 dephosphorylates specifically TSC2 at sites, associated with its activation via AMP kinase (AMPK) pathway. Taken together, these results suggest that PP5 exerts negative regulation on TSC1/2 function through dephosphorylation of AMPK-mediated sites. Вперше показано, що туберозно-склерозний комплекс 2 (TSC2) специфічно взаємодіє з протеїнфосфатазою 5 (PP5) у клітинах ссавців. Така взаємодія є характерною для клітин, що перебувають у фазі експоненційного росту, а також у стимульованих сироваткою клітинах. Встановлено, що PP5 дефосфорилює TSC2 по сайтах, специфічних для AMP кінази (AMPK) і відповідно може відігравати негативну роль у регуляції активності TSC1/2 комплексу. Впервые показано, что туберозно-склерозный комплекс 2 (TSC2) специфически взаимодействует с протеинфосфатазой 5 (PP5) в клетках млекопитающих. Данное взаимодействие является характерным для клеток, находящихся в фазе экспоненциального роста, а также в стимулированных сывороткой клетках. Установлено, что PP5 дефосфорилирует TSC2 по сайтам, специфичным для AMP киназы (AMPK) и соответственно может играть негативную роль в регуляции активности TSC1/2 комплекса. en Інститут молекулярної біології і генетики НАН України Біополімери і клітина Короткі повідомлення Dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5 Серин/треониновая протеинфосфатаза 5 дефосфорилирует туберозно-склерозный комплекс 2 Серин/треонінова протеїнфосфатаза 5 дефосфорилює туберозно-склерозний комплекс 2 Article published earlier |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| title |
Dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5 |
| spellingShingle |
Dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5 Malanchuk, O.M. Palchevskyy, S.S. Filonenko, V.V. Короткі повідомлення |
| title_short |
Dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5 |
| title_full |
Dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5 |
| title_fullStr |
Dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5 |
| title_full_unstemmed |
Dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5 |
| title_sort |
dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5 |
| author |
Malanchuk, O.M. Palchevskyy, S.S. Filonenko, V.V. |
| author_facet |
Malanchuk, O.M. Palchevskyy, S.S. Filonenko, V.V. |
| topic |
Короткі повідомлення |
| topic_facet |
Короткі повідомлення |
| publishDate |
2008 |
| language |
English |
| container_title |
Біополімери і клітина |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| format |
Article |
| title_alt |
Серин/треониновая протеинфосфатаза 5 дефосфорилирует туберозно-склерозный комплекс 2 Серин/треонінова протеїнфосфатаза 5 дефосфорилює туберозно-склерозний комплекс 2 |
| description |
We report here for the first time specific interaction between tuberous sclerosis complex 2 (TSC2) and protein phosphatase 5 (PP5) in mammalian cells. We found that the interaction is stronger in exponentially growing and serum stimulated cells when compared to serum starved cells. In addition, we provide the evidence that PP5 dephosphorylates specifically TSC2 at sites, associated with its activation via AMP kinase (AMPK) pathway. Taken together, these results suggest that PP5 exerts negative regulation on TSC1/2 function through dephosphorylation of AMPK-mediated sites.
Вперше показано, що туберозно-склерозний комплекс 2 (TSC2) специфічно взаємодіє з протеїнфосфатазою 5 (PP5) у клітинах ссавців. Така взаємодія є характерною для клітин, що перебувають у фазі експоненційного росту, а також у стимульованих сироваткою клітинах. Встановлено, що PP5 дефосфорилює TSC2 по сайтах, специфічних для AMP кінази (AMPK) і відповідно може відігравати негативну роль у регуляції активності TSC1/2 комплексу.
Впервые показано, что туберозно-склерозный комплекс 2 (TSC2) специфически взаимодействует с протеинфосфатазой 5 (PP5) в клетках млекопитающих. Данное взаимодействие является характерным для клеток, находящихся в фазе экспоненциального роста, а также в стимулированных сывороткой клетках. Установлено, что PP5 дефосфорилирует TSC2 по сайтам, специфичным для AMP киназы (AMPK) и соответственно может играть негативную роль в регуляции активности TSC1/2 комплекса.
|
| issn |
0233-7657 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/157679 |
| citation_txt |
Dephosphorylation of tuberous sclerosis complex 2 by serine/threonine protein phosphatase 5 / O.M. Malanchuk, S.S. Palchevskyy, V.V. Filonenko // Біополімери і клітина. — 2008. — Т. 24, № 2. — С. 176-179. — Бібліогр.: 16 назв. — англ. |
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2025-11-24T16:49:09Z |
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2025-11-24T16:49:09Z |
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1850482926383267840 |
| fulltext |
SHORT COMMUNICATIONS
Dephosphorylation of tuberous sclerosis complex 2
by serine/threonine protein phosphatase 5
O. M. Malanchuk1,2, S. S. Palchevskyy1, V. V. Filonenko1
1Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine
150 Zabolotnogo Str., Kyiv 03680, Ukraine
2National Taras Shevchenko University of Kyiv
2 Academician Glushkov av., Kyiv, 03127, Ukraine
filonenko@imbg.org.ua
We report here for the first time specific interaction between tuberous sclerosis complex 2 (TSC2) and
protein phosphatase 5 (PP5) in mammalian cells. We found that the interaction is stronger in exponentially
growing and serum stimulated cells when compared to serum starved cells. In addition, we provide the
evidence that PP5 dephosphorylates specifically TSC2 at sites, associated with its activation via AMP
kinase (AMPK) pathway. Taken together, these results suggest that PP5 exerts negative regulation on
TSC1/2 function through dephosphorylation of AMPK-mediated sites.
Keywords: protein phosphatase 5, tuberous sclerosis complex 2, dephosphorylation.
Introduction. TSC2 (tuberin) is a 200 kDa tumour
suppressor protein, which forms a functional complex
with TSC1 (hamartin). In this complex TSC2 is the
catalytic subunit possessing GTPase-activating protein
(GAP) activity towards Rheb, a Ras family GTPase [2].
Genetic and biochemical data indicate that Rheb
functions downstream of TSC2 and upstream of mTOR
(mammalian target of rapamycin [3–5]. Rheb-induced
activation of the mTOR pathway stimulates the
phosphorylation of two translational regulators, S6K
(ribosomal S6 kinase 1) and 4EBP1 (eukaryotic
initiation factor 4E binding protein 1) [2, 6].
Deregulation of TSC1/TSC2 complex has been
implicated in pathogenesis of tuberous sclerosis, an
autosomal-dominant disorder, associated with the
development of hamartomas in almost every organ,
most notably in brain, kidneys, heart, and eyes [1].
The activity of TSC2 is regulated by multiple
phosphorylations mediated by diverse protein kinases,
including PKB/Akt, RSK1, ERK, MK2, and AMPK
[7–10]. Therefore, TSC1/TSC2 complex integrates
signals from multiple signalling pathways and
influences diverse cellular functions through negative
regulation of the mTOR pathway [8, 11, 12].
Although the mechanisms of TSC2 regulation by
protein kinases were studied extensively, little is
known so far about phosphotase(s) catalyzing
dephosphorylation of this protein. Previously we have
reported that serine/threonine protein phosphatase 5
(PP5) is a novel binding partner of TSC2 [13].
Furthermore, we demonstrated that PP5 interacts
specifically with TSC2 not only in yeast two-hybrid
system, but also in mammalian cells [14]. In order to
establish functional link between TSC1/TSC2 and PP5
we studied the protein complex formation in starved
cells and in response to serum stimulation.
176
ISSN 0233-7657. Biopolymers and cell. 2008. Vol. 24. N 2
Ó O. M. MALANCHUK, S. S. PALCHEVSKYY, V. V. FILONENKO, 2008
Additionally, we tested whether dephosphorylation of
TSC2 could be mediated by PP5.
Materials and Methods. Culturing and
transfection of TSC2+/+ p53–/– mouse embryonic
fibroblasts (MEFs) was described previously in [14].
The production of anti-TSC2 mAbs (D6) is described in
[15]. Polyclonal anti-PP5 antibody was purchased from
Cell Signaling and anti-Myc mAb was from
«Invitrogen» (USA). Cell lysate preparation, Western
blot analysis and immunoprecipitation of TSC2/PP5
protein complex have been performed according to
[15]. Recombinant PP5 was purified from insect cells,
infected with recombinant baculovirus. Enzymatically
active AMPK was presented by Dr M Sanders and Prof.
D. Carling, MRC Centre, London.
TSC2 was immunoprecipitated from TSC2+/+ p53–/–
MEFs cells lysate (100 mg) using antibody (anti-TSC2
mAb D6) coupled to Protein A Sepharose beads.
Immunoprecipitates were incubated with 1 ml of AMPK
for 30 min at 37 °C in a final volume of 25 ml of kinase
buffer (50 mM HEPES, pH 7.3, 1 mM DTT, 50 mM
NaCl, 2.5 mM MgCl2, 0.1 mM ATP, 2.5 mCi of
[g-32P]ATP). Then, beads were washed in phosphatase
assay buffer (60 mM Tris-HCl, pH 7.6, 1 mM EDTA,
1 mM EGTA, 0.1% b-mercaptoethanol). PP5
phosphatase assay was performed in a reaction mixture
(25 ml) containing 1 mg of recombinant PP5 and 200 mM
of arachidonic acid at 30 °C for 2 hrs. Reaction was
terminated by the addition of SDS-PAGE sample
buffer. Samples were boiled for 4 min and subjected to
SDS-PAGE. The level of TSC2 phosphorylation was
measured by autoradiography.
Results and Discussion. To analyze the interaction
between TSC2 and PP5 in cells under different growth
conditions, we have applied the immunoprecipitation
assay followed by Western blotting. Initially TSC2+/+
p53–/– MEFs expressing TSC2 at high level [14], were
transiently transfected with pcDNA3.1/Myc-PP5
construct. Western blot analysis of cell lysates with
specific antibodies confirmed the expression of
recombinant Myc-PP5 (Fig. 1, A). Then, transfected
cells were grown exponentially or serum starved for
24 hours, and afterwards, were stimulated with 10 %
FCS for one hour. The extracts were prepared from
harvested cells and used in the immunoprecipitaiton
assay. D6-TSC2 and anti-Myc antibodies were coupled
to Protein A Sepharose and used to immunoprecipitate
TSC2 and Myc-PP5 respectively. Immune complexes
were separated by SDS-PAGE and analyzed by
immunoblotting with specific antibodies.
As shown in Fig. 1, Myc-PP5 is detected in
anti-TSC2 immune complexes and vise versa, TSC2
co-immunoprecipitates with Myc-PP5 in all analyzed
samples. However, the interaction between Myc-PP5
and TSC2 was reproducibly weaker in serum starved
cells, when compared to exponentially growing and
serum-stimulated cells (Fig. 1, B, lanes 6–8 and 10–12).
TSC1/2 complex is known to be a negative
regulator of cell growth and mTOR signaling pathway.
Therefore, its activity should be tightly controlled in
growing and proliferating cells [2–6]. It is well
established that several protein kinases phosphorylate
TSC2 in vivo in response to various extracellular
stimuli. For example, when cells are stimulated by
growth factors or serum, the phosphophorylation of
177
DEPHOSPHORYLATION OF TUBEROUS SCLEROSIS COMPLEX 2 BY SERINE/ THREONINE PHOSPHATASE 5
Fig. 1. Western blot analysis of TSC2 and PP5 in cell lysates (A) and
anti-D6 and anti-Myc immunoprecipitates (B). TSC2+/+ p53–/– MEFs
were transiently transfected with pcDNA3.1 (lanes 1, 9) or
pcDNA3.1/myc-PP5 (lanes 2–4, 5–8 and 10–12). Two days after
transfection, TSC2 and Myc-PP5 were immunoprecipitated from
cell extracts using mAb D6 (lanes 6–8) and anti-Myc (lanes 9–12).
Protein A Sepharose was used to bring down immune complexes,
which were then resolved by SDS-PAGE and immunoblotted with
indicated antibodies. Cell lysates from TSC2+/+ p53–/– MEFs were
incubated with Protein A Sepharose without mAbs (lane 5); 1, 9 –
supernatant of exponentially growing TSC2+/+ p53–/– MEFs,
transiently transfected by pcDNA3.1; 6, 10 – supernatant of
exponentially growing TSC2+/+, p53–/– MEFs, transiently transfected
by pcDNA3.1-PP5-Myc; 7, 11 – supernatant of serum starved
TSC2+/+ p53–/– MEFs, transiently transfected by
pcDNA3.1-PP5-Myc; 8, 12 – supernatant of serum restimulated
TSC2+/+ p53–/– MEFs, transiently transfected by
pcDNA3.1-PP5-Myc
TSC2 by PKB/Akt at several sites is known to inhibit
its cellular functions.
On the other hand, AMP activated protein kinase
(AMPK) is a cellular energy sensor and it plays an
important role in the regulation of TSC2 activity [16].
AMPK-mediated phosphorylation of TSC2 at Ser 1345
induces its GAP activity towards small GTPase Rheb,
resulting in its inactivation [8]. To explore a potential
effect of PP5 on TSC2 phosphorylation status, we
determine the phosphatase activity of PP5 towards
TSC2 phosphorylated by AMPK.
In this analysis TSC2 was immunoprecipitated
from exponently growing TSC2+/+ p53–/– MEFs and
then phosphorylated in vitro by AMPK kinase as
described in «Materials and Methods». Then,
pre-phosphorylated TSC2 was used as s substrate for
PP5 in a phosphatase assay. According to the data
presented in Fig. 2 PP5 reproducibly dephosphorylated
TSC2 at AMPK specific sites.
To summarize, data presented in this report indicate
that TSC2 interacts with PP5 in vivo and efficiency of
such interaction depends on physiological status of
cells. In addition, we demonstrated that PP5 is capable
of dephosphorylating TSC2 in vitro at AMPK specific
sites. Our data suggest that the physiological relevance
of TSC2/PP5 interaction might be in reversing the
stimulatory signaling mediated by AMPK on TSC2
activity.
Acknowledgements. The work of O. M. Malanchuk
was supported by UNESCO fellowship.
O. M. Mà ëàí ÷óê, Ñ. Ñ. Ïàëü ÷å âñüêèé, Â. Â. Ô³ëî íåí êî
Ñå ðèí/òðå îí³íîâà ïðî òå¿ íôîñ ôà òà çà 5 äå ôîñ ôî ðè ëþº
òó áå ðîç íî-ñêëå ðîç íèé êîì ïëåêñ 2
Ðå çþ ìå
Âïåð øå ïî êà çà íî, ùî òó áå ðîç íî-ñêëå ðîç íèé êîì ïëåêñ 2 (TSC2)
ñïå öèô³÷íî âçàºìî䳺 ç ïðî òå¿ íôîñ ôà òà çîþ 5 (PP5) ó êë³òè -
íàõ ññàâö³â. Òàêà âçàºìîä³ÿ º õà ðàê òåð íîþ äëÿ êë³òèí, ùî ïå ðå -
áó âà þòü ó ôàç³ åê ñïî íåíö³éíî ãî ðîñ òó, à òà êîæ ó
ñòè ìóëü î âà íèõ ñè ðî âàò êîþ êë³òè íàõ. Âñòà íîâ ëå íî, ùî PP5
äå ôîñ ôî ðè ëþº TSC2 ïî ñàé òàõ, ñïå öèô³÷íèõ äëÿ AMP ê³íàçè
(AMPK) ³ â³äïîâ³äíî ìîæå â³ä³ãðà âà òè íå ãà òèâ íó ðîëü ó ðå ãó -
ëÿö³¿ àê òèâ íîñò³ TSC1/2 êîì ïëåê ñó.
Êëþ ÷îâ³ ñëî âà: ñå ðèí/òðå îí³íîâà ïðî òå¿ íôîñ ôà òà çà 5, òó -
áå ðîç íî-ñêëå ðîç íèé êîì ïëåêñ 2,äå ôîñ ôî ðè ëþ âàí íÿ.
O. Í. Mà ëàí ÷óê, Ñ. Ñ. Ïàëü ÷åâ ñêèé, Â. Â. Ôè ëî íåí êî
Ñå ðèí/òðå î íè íî âàÿ ïðî òå èí ôîñ ôà òà çà 5 äå ôîñ ôî ðè ëè ðó åò
òó áå ðîç íî-ñêëå ðîç íûé êîì ïëåêñ 2
Ðå çþ ìå
Âïåð âûå ïî êà çà íî, ÷òî òó áå ðîç íî-ñêëå ðîç íûé êîì ïëåêñ 2
(TSC2) ñïå öè ôè ÷åñ êè âçà è ìî äå éñòâó åò ñ ïðî òå èí ôîñ ôà òà çîé
5 (PP5) â êëåò êàõ ìëå êî ïè òà þ ùèõ. Äàí íîå âçà è ìî äå éñòâèå ÿâ -
ëÿ åò ñÿ õà ðàê òåð íûì äëÿ êëå òîê, íà õî äÿù èõñÿ â ôàçå ýêñ ïî -
íåí öè àëü íî ãî ðîñ òà, à òàê æå â ñòè ìó ëè ðî âàí íûõ ñû âî ðîò êîé
êëåò êàõ. Óñòà íîâ ëå íî, ÷òî PP5 äå ôîñ ôî ðè ëè ðó åò TSC2 ïî
ñàé òàì, ñïå öè ôè÷ íûì äëÿ AMP êè íà çû (AMPK) è ñî îò âå -
òñòâåí íî ìî æåò èã ðàòü íå ãà òèâ íóþ ðîëü â ðå ãó ëÿ öèè àê òèâ -
íîñ òè TSC1/2 êîì ïëåê ñà.
Êëþ ÷å âûå ñëî âà: ñå ðèí/òðå î íè íî âàÿ ïðî òå èí ôîñ ôà òà çà 5,
òó áå ðîç íî-ñêëå ðîç íûé êîì ïëåêñ 2, äå ôîñ ôî ðè ëè ðî âà íèå.
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MALANCHUK O. M., PALCHEVSKYY S. S., FILONENKO V. V.
Figure 2. Dephosphorylation of TSC2 by recombinant PP5: A –
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UDC 577.218; 616-006
Received 28.01.08
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DEPHOSPHORYLATION OF TUBEROUS SCLEROSIS COMPLEX 2 BY SERINE/ THREONINE PHOSPHATASE 5
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