共查询到20条相似文献,搜索用时 31 毫秒
1.
PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth 总被引:13,自引:0,他引:13
Akt/protein kinase B critically regulates the balance between cell survival and apoptosis. Phosphorylation of Akt at two key sites, the activation loop and the hydrophobic motif, activates the kinase and promotes cell survival. The mechanism of dephosphorylation and signal termination is unknown. Here, we identify a protein phosphatase, PH domain leucine-rich repeat protein phosphatase (PHLPP), that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1), triggering apoptosis and suppressing tumor growth. The effects of PHLPP on apoptosis are prevented in cells expressing an S473D construct of Akt, revealing that the hydrophobic motif is the primary cellular target of PHLPP. PHLPP levels are markedly reduced in several colon cancer and glioblastoma cell lines that have elevated Akt phosphorylation. Reintroduction of PHLPP into a glioblastoma cell line causes a dramatic suppression of tumor growth. These data are consistent with PHLPP terminating Akt signaling by directly dephosphorylating and inactivating Akt. 相似文献
2.
Mei Hua Gao Tong Tang Atsushi Miyanohara James R. Feramisco H. Kirk Hammond 《Cellular signalling》2010,22(4):584-589
Adenylyl cyclase type 6 (AC6) and the β1 adrenergic receptor (β1AR) are pivotal proteins in transmembrane βAR-signaling in cardiac myocytes. Increased expression of AC6 has beneficial effects on the heart, but increased β1AR expression has marked deleterious effects. Why do these two elements of the βAR pathway have such different effects? Using adenovirus-mediated gene transfer of the two transgenes in neonatal rat cardiac myocytes, we assessed cellular distribution and performed selected biochemical assays. β1AR was found predominantly in the plasma membrane. In contrast, AC6 was found in the plasma membrane but also was associated with the nuclear envelope, sarcoplasmic reticulum, mitochondria, and cytoplasm. Increased β1AR, but not AC6, increased follistatin expression, p38 phosphorylation, phosphatidylserine translocation to the PM, and apoptosis. In contrast, increased AC6, but not β1AR, inhibited PHLPP2 activity, activated PI3K and Akt, and increased p70S6 kinase phosphorylation and Bcl-2 expression; apoptosis was unchanged. The distribution of AC6 to multiple cellular compartments appears to enable interactions with other proteins (e.g., PHLPP2) and activates cardioprotective signaling (PI3K/Akt). In contrast, β1AR, confined to the plasma membrane, increased phosphatidylserine translocation and apoptosis. These data provide a potential underlying mechanism for the beneficial vs deleterious effects of these two related βAR-signaling elements. 相似文献
3.
4.
Precise balance between phosphorylation, catalyzed by protein kinases, and dephosphorylation, catalyzed by protein phosphatases, is essential for cellular homeostasis. Deregulation of this balance leads to pathophysiological states that drive diseases such as cancer, heart disease, and diabetes. The recent discovery of the PHLPP (pleckstrin homology domain leucine-rich repeat protein phosphatase) family of Ser/Thr phosphatases adds a new player to the cast of phosphate-controlling enzymes in cell signaling. PHLPP isozymes catalyze the dephosphorylation of a conserved regulatory motif, the hydrophobic motif, on the AGC kinases Akt, PKC, and S6 kinase, as well as an inhibitory site on the kinase Mst1, to inhibit cellular proliferation and induce apoptosis. The frequent deletion of PHLPP in cancer, coupled with the development of prostate tumors in mice lacking PHLPP1, identifies PHLPP as a novel tumor suppressor. This minireview discusses the structure, function, and regulation of PHLPP, with particular focus on its role in disease. 相似文献
5.
PH domain leucine-rich repeat protein phosphatase (PHLPP) is a family of enzymes made up of two isoforms (PHLPP1 and PHLPP2), whose actions modulate intracellular activity via the dephosphorylation of specific serine/threonine (Ser/Thr) residues on proteins such as Akt. Recent data generated in our lab, supported by findings from others, implicates the divergent roles of PHLPP1 and PHLPP2 in maintaining cellular homeostasis since dysregulation of these enzymes has been linked to various pathological states including cardiovascular disease, diabetes, ischemia/reperfusion injury, musculoskeletal disease, and cancer. Therefore, development of therapies to modulate specific isoforms of PHLPP could prove to be therapeutically beneficial in several diseases especially those targeting the cardiovascular system. This review is intended to provide a comprehensive summary of current literature detailing the role of the PHLPP isoforms in the development and progression of heart disease. 相似文献
6.
John Brognard Matthew Niederst Gloria Reyes Noel Warfel Alexandra C. Newton 《The Journal of biological chemistry》2009,284(22):15215-15223
PHLPP2 (PH domain leucine-rich repeat protein phosphatase 2) terminates Akt
and protein kinase C (PKC) activity by specifically dephosphorylating these
kinases at a key regulatory site, the hydrophobic motif (Ser-473 in Akt1).
Here we identify a polymorphism that results in an amino acid change from a
Leu to Ser at codon 1016 in the phosphatase domain of PHLPP2, which reduces
phosphatase activity toward Akt both in vitro and in cells, in turn
resulting in reduced apoptosis. Depletion of endogenous PHLPP2 variants in
breast cancer cells revealed the Ser-1016 variant is less functional toward
both Akt and PKC. In pair-matched high grade breast cancer samples we observed
retention of only the Ser allele from heterozygous patients (identical results
were observed in a pair-matched normal and tumor cell line). Thus, we have
identified a functional polymorphism that impairs the activity of PHLPP2 and
correlates with elevated Akt phosphorylation and increased PKC levels.Breast cancer is diagnosed in ∼180,000 women and is the cause of 40,000
deaths each year in the
U.S.2 A prevalent
underlying mechanism driving tumorigenesis is aberrant signal transduction
pathways that result in constitutive activation of cell growth, proliferation,
and survival pathways (2). A
well characterized signal transduction pathway in breast cancer that promotes
cellular survival, growth, and proliferation is the phosphatidylinositol
3-kinase/Akt pathway (3). This
pathway is activated by a number of mechanisms, including gene amplification
or gain of function mutations in upstream receptor protein-tyrosine kinases
(4,
5), constitutive activation of
hormone receptors (6),
activating mutations in phosphatidylinositol 3-kinase and Akt
(7,
8), and loss of function
mutations in the regulatory phosphatase
PTEN3 (phosphatase and
tensin homolog on chromosome ten)
(9). Thus, Akt is a major
regulator of breast tumorigenesis.There are three isoforms of Akt present in humans. All three isoforms
contain activating phosphorylation sites in the activation loop (Thr-308 in
Akt1) and in the C-terminal hydrophobic motif (Ser-473 in Akt1)
(10). Upon growth factor
receptor stimulation, phosphatidylinositol 3-kinase becomes activated and
phosphorylates the D3 position of, typically, phosphatidylinositol
(4,
5) bisphosphate to generate
phosphatidylinositol (3,4,5)-trisphosphate
(11). This
3′-phosphorylated lipid recruits Akt to the plasma membrane by binding
to its PH domain, resulting in conformational changes that allow access to the
activation loop phosphorylation site
(11). Constitutively bound
phosphatidylinositol-dependent kinase-1 then phosphorylates Akt at Thr-308,
accompanied by phosphorylation at Ser-473 resulting in a catalytically active
kinase (12). Phosphorylation
of Ser-473 depends on the mTORC2 complex
(13-16).
Signaling through this pathway is terminated by removal of the lipid second
messenger phosphatidylinositol (3,4,5)-trisphosphate catalyzed by the
phosphatase PTEN and by direct dephosphorylation of Akt by the
recently-identified PHLPP family of phosphatases and protein phosphatase
2A-type phosphatases
(17-20).The PHLPP family of phosphatases comprise three variants, the alternatively
spliced PHLPP1α and PHLPP1β, and PHLPP2
(21). PHLPP1 and PHLPP2
specifically dephosphorylate the hydrophobic motif of specific Akt isozymes,
thus decreasing Akt activity and promoting apoptosis
(18,
19). PHLPP2 binds and
dephosphorylates Akt1 and Akt3, whereas PHLPP1 binds and dephosphorylates Akt2
and Akt3 (18,
22). Their role in
inactivating Akt suggests that both PHLPP1 and PHLPP2 could be potential tumor
suppressors. Consistent with such a role, these phosphatases also
dephosphorylate the hydrophobic motif of PKC, resulting in degradation of PKC.
For this kinase, phosphorylation stabilizes the enzyme, so that the effect of
depletion of the PHLPP phosphatases is to increase PKC protein levels
(23). PKC is a well
characterized oncogene, and loss of function of the PHLPP phosphatases could
increase PKC protein levels and promote tumorigenesis
(24). Providing further
rationale that PHLPP2 could be a potential tumor suppressor, the phosphatase
is located on chromosome 16q22.3, a region that encounters frequent loss of
heterozygosity (LOH) in many primary and malignant breast tumors
(25).Here we identify a non-synonymous polymorphism that results in an amino
acid change from a Leu to a Ser at codon 1016 in the PP2C phosphatase domain
of PHLPP2. Overexpression studies reveal the Ser-1016 variant has impaired
phosphatase activity and is less effective at inducing apoptosis than the
Leu-1016 variant. When comparing a pair-matched normal and breast cancer cell
line or pair-matched normal and high grade tumor patient samples that are
heterozygous, we observe preferential loss of the Leu allele in the tumor
tissue or breast cancer cell line. This observation provides evidence that
PHLPP2 could be one of the elusive tumor suppressor genes on chromosome 16q,
and for heterozygous patients, loss of the more catalytically active Leu-1016
may promote breast tumorigenesis. 相似文献
7.
Pankov R Cukierman E Clark K Matsumoto K Hahn C Poulin B Yamada KM 《The Journal of biological chemistry》2003,278(20):18671-18681
Integrin transmembrane receptors generate multiple signals, but how they mediate specific signaling is not clear. Here we test the hypothesis that particular sequences along the beta(1) integrin cytoplasmic domain may exist that are intimately related to specific integrin-mediated signaling pathways. Using systematic alanine mutagenesis of amino acids conserved between different beta integrin cytoplasmic domains, we identified the tryptophan residue at position 775 of human beta(1) integrin as specific and necessary for integrin-mediated protein kinase B/Akt survival signaling. Stable expression of a beta(1) integrin mutated at this amino acid in GD25 beta(1)-null cells resulted in reduction of Akt phosphorylation at both Ser(473) and Thr(308) activation sites. As a consequence, the cells were substantially more sensitive to serum starvation-induced apoptosis when compared with cells expressing wild type beta(1) integrin. This inactivation of Akt resulted from increased dephosphorylation by a localized active population of protein phosphatase 2A. Both Akt and protein phosphatase 2A were present in beta(1) integrin-organized cytoplasmic complexes, but the activity of this phosphatase was 2.5 times higher in the complexes organized by the mutant integrin. The mutation of Trp(775) specifically affected Akt signaling, without effects on other integrin-activated pathways including phosphoinositide 3-kinase, MAPK, JNK, and p38 nor did it influence activation of the integrin-responsive kinases focal adhesion kinase and Src. The identification of Trp(775) as a specific site for integrin-mediated Akt signaling supports the concept of specificity of signaling along the integrin cytoplasmic domain. 相似文献
8.
9.
Tracy M. Crotty Tomoyuki Nakano Diana M. Stafforini Matthew K. Topham 《The Journal of biological chemistry》2013,288(3):1439-1447
Discovering proteins that modulate Akt signaling has become a critical task, given the oncogenic role of Akt in a wide variety of cancers. We have discovered a novel diacylglycerol signaling pathway that promotes dephosphorylation of Akt. This pathway is regulated by diacylglycerol kinase δ (DGKδ). In DGKδ-deficient cells, we found reduced Akt phosphorylation downstream of three receptor tyrosine kinases. Phosphorylation upstream of Akt was not affected. Our data indicate that PKCα, which is excessively active in DGKδ-deficient cells, promotes dephosphorylation of Akt through pleckstrin homology domain leucine-rich repeats protein phosphatase (PHLPP) 2. Depletion of either PKCα or PHLPP2 rescued Akt phosphorylation in DGKδ-deficient cells. In contrast, depletion of PHLPP1, another Akt phosphatase, failed to rescue Akt phosphorylation. Other PHLPP substrates were not affected by DGKδ deficiency, suggesting mechanisms allowing specific modulation of Akt dephosphorylation. We found that β-arrestin 1 acted as a scaffold for PHLPP2 and Akt1, providing a mechanism for specificity. Because of its ability to reduce Akt phosphorylation, we tested whether depletion of DGKδ could attenuate tumorigenic properties of cultured cells and found that DGKδ deficiency reduced cell proliferation and migration and enhanced apoptosis. We have, thus, discovered a novel pathway in which diacylglycerol signaling negatively regulates Akt activity. Our collective data indicate that DGKδ is a pertinent cancer target, and our studies could lay the groundwork for development of novel cancer therapeutics. 相似文献
10.
PHLPP1 (PH domain leucine-rich-repeats protein phosphatase) is a Ser/Thr protein phosphatase that acts as a tumour suppressor by negatively regulating Akt. Here, we show that PHLPP1 is recruited to the cell membrane by binding to a scaffolding protein: Scribble. Knockdown of Scribble (Scrib) results in redistribution of PHLPP1 from the membrane to the cytoplasm and an increase in Akt phosphorylation, whereas overexpression of Scrib has the opposite effect. Furthermore, PHLPP1-dependent inhibition of cell proliferation is facilitated by the formation of a Scrib, PHLPP1 and Akt trimeric complex. Thus, our findings identify a functional interaction between PHLPP1 and Scrib in negatively regulating Akt signalling. 相似文献
11.
PHLPP is a family of Ser/Thr protein phosphatases that contains PHLPP1 and PHLPP2 isoforms. We have shown previously that PHLPP functions as a tumor suppressor by negatively regulating Akt signaling in cancer cells. Here we report the identification of ribosomal protein S6 kinase 1 (S6K1) as a novel substrate of PHLPP. Overexpression of both PHLPP isoforms resulted in a decrease in S6K1 phosphorylation in cells, and this PHLPP-mediated dephosphorylation of S6K1 was independent of its ability to dephosphorylate Akt. Conversely, S6K1 phosphorylation was increased in cells depleted of PHLPP expression. Furthermore, we showed that the insulin receptor substrate 1 (IRS-1) expression and insulin-induced Akt phosphorylation were significantly decreased as the result of activation of the S6K-dependent negative feedback loop in PHLPP knockdown cells. Functionally, the phosphorylation of ribosomal protein S6 (rpS6) and the amount of phosphorylated rpS6 bound to the translation initiation complex were increased in PHLPP-knockdown cells. This correlated with increased cell size, protein content, and rate of cap-dependent translation. Taken together, our results demonstrate that loss of PHLPP expression activates the S6K-dependent negative feedback loop and that PHLPP is a novel player involved in regulating protein translation initiation and cell size via direct dephosphorylation of S6K1. 相似文献
12.
The life cycle of protein kinase C (PKC) is controlled by multiple phosphorylation and dephosphorylation steps. The maturation of PKC requires three ordered phosphorylations, one at the activation loop and two at COOH-terminal sites, the turn motif and the hydrophobic motif, to yield a stable and signaling-competent enzyme. Dephosphorylation of the enzyme leads to protein degradation. We have recently discovered a novel family of protein phosphatases named PH domain leucine-rich repeat protein phosphatase (PHLPP) whose members terminate Akt signaling by dephosphorylating the hydrophobic motif on Akt. Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle. Deletion mutagenesis reveals that the PH domain is necessary for the effective dephosphorylation of PKC betaII by PHLPP in cells, whereas the PDZ-binding motif, required for Akt regulation, is dispensable. The phorbol ester-mediated dephosphorylation of the hydrophobic site, but not the turn motif or activation loop, is insensitive to okadaic acid, consistent with PHLPP, a PP2C family member, controlling the hydrophobic site. In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha. Last, we show that depletion of PHLPP in colon cancer and normal breast epithelial cells results in an increase in conventional and novel PKC levels. These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation. 相似文献
13.
Kageyama K Ihara Y Goto S Urata Y Toda G Yano K Kondo T 《The Journal of biological chemistry》2002,277(22):19255-19264
Calreticulin is a Ca(2+)-binding molecular chaperone of the lumen of the endoplasmic reticulum. Calreticulin has been shown to be essential for cardiac and neural development in mice, but the mechanism by which it functions in cell differentiation is not fully understood. To examine the role of calreticulin in cardiac differentiation, the calreticulin gene was introduced into rat cardiomyoblast H9c2 cells, and the effect of calreticulin overexpression on cardiac differentiation was examined. Upon culture in a differentiation medium containing fetal calf serum (1%) and retinoic acid (10 nm), cells transfected with the calreticulin gene were highly susceptible to apoptosis compared with controls. In the gene-transfected cells, protein kinase B/Akt signaling was significantly suppressed during differentiation. Furthermore, protein phosphatase 2A, a Ser/Thr protein phosphatase, was significantly up-regulated, implying suppression of Akt signaling due to dephosphorylation of Akt by the up-regulated protein phosphatase 2A via regulation of Ca(2+) homeostasis. Thus, overexpression of calreticulin promotes differentiation-dependent apoptosis in H9c2 cells by suppressing the Akt signaling pathway. These findings indicate a novel mechanism by which cytoplasmic Akt signaling is modulated to cause apoptosis by a resident protein of the endoplasmic reticulum, calreticulin. 相似文献
14.
De-Xiang Zhuo Xiao-Wei Zhang Bo Jin Zheng Zhang Bu-Shan Xie Cheng-Lin Wu Kan Gong Ze-Bin Mao 《PloS one》2013,8(6)
Akt/protein kinase B is a pivotal component downstream of phosphatidylinositol 3-kinase (PI3K) pathway, whose activity regulates the balance between cell survival and apoptosis. Phosphorylation of Akt occurs at two key sites either at Thr308 site in the activation loop or at Ser473 site in the hydrophobic motif. The phosphorylated form of Akt (pAkt) is activated to promote cell survival. The mechanisms of pAkt dephosphorylation and how the signal transduction of Akt pathway is terminated are still largely unknown. In this study, we identified a novel protein phosphatase CSTP1(complete s transactivated protein 1), which interacts and dephosphorylates Akt specifically at Ser473 site in vivo and in vitro, blocks cell cycle progression and promotes cell apoptosis. The effects of CSTP1 on cell survival and cell cycle were abrogated by depletion of phosphatase domain of CSTP1 or by expression of a constitutively active form of Akt (S473D), suggesting Ser473 site of Akt as a primary cellular target of CSTP1. Expression profile analysis showed that CSTP1 expression is selectively down-regulated in non-invasive bladder cancer tissues and over-expression of CSTP1 suppressed the size of tumors in nude mice. Kaplan-Meier curves revealed that decreased expression of CSTP1 implicated significantly reduced recurrence-free survival in patients suffered from non-invasive bladder cancers. 相似文献
15.
16.
Thayyullathil F Chathoth S Shahin A Kizhakkayil J Hago A Patel M Galadari S 《Journal of cellular biochemistry》2011,112(4):1138-1153
Sphingosine (SPH) is an important bioactive lipid involved in mediating a variety of cell functions including apoptosis. However, the signaling mechanism of SPH-induced apoptosis remains unclear. We have investigated whether SPH inhibits survival signaling in cells by inhibiting Akt kinase activity. This study demonstrates that treatment of Jurkat cells with SPH leads to Akt dephosphorylation as early as 15 min, and the cells undergo apoptosis after 6 h. This Akt dephosphorylation is not mediated through deactivation of upstream kinases, since SPH does not inhibit the upstream phosphoinositide-dependent kinase 1 (PDK1) phosphorylation. Rather, sensitivity to the Ser/Thr protein phosphatase inhibitors (calyculin A, phosphatidic acid, tautomycin, and okadaic acid) indicates an important role for protein phosphatase 1 (PP1) in this process. In vitro phosphatase assay, using Akt immunoprecipitate following treatment with SPH, reveals an increase in Akt-PP1 association as determined by immunoprecipitation analysis. Moreover, SPH-induced dephosphorylation of Akt at Ser(473) subsequently leads to the activation of GSK-3β, caspase 3, PARP cleavage, and ultimately apoptosis. Pre-treatment with caspase 3 inhibitor z-VAD-fmk and Ser/Thr phosphatase inhibitor abrogates the effect of SPH on facilitating apoptosis. Altogether, these results demonstrate that PP1-mediated inhibition of the key anti-apoptotic protein, Akt, plays an important role in SPH-mediated apoptosis in Jurkat cells. 相似文献
17.
PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms 总被引:7,自引:0,他引:7
Akt/protein kinase B controls cell growth, proliferation, and survival. We recently discovered a novel phosphatase PHLPP, for PH domain leucine-rich repeat protein phosphatase, which terminates Akt signaling by directly dephosphorylating and inactivating Akt. Here we describe a second family member, PHLPP2, which also inactivates Akt, inhibits cell-cycle progression, and promotes apoptosis. These phosphatases control the amplitude of Akt signaling: depletion of either isoform increases the magnitude of agonist-evoked Akt phosphorylation by almost two orders of magnitude. Although PHLPP1 and PHLPP2 both dephosphorylate the same residue (hydrophobic phosphorylation motif) on Akt, they differentially terminate Akt signaling by regulating distinct Akt isoforms. Knockdown studies reveal that PHLPP1 specifically modulates the phosphorylation of HDM2 and GSK-3alpha through Akt2, whereas PHLPP2 specifically modulates the phosphorylation of p27 through Akt3. Our data unveil a mechanism to selectively terminate Akt-signaling pathways through the differential inactivation of specific Akt isoforms by specific PHLPP isoforms. 相似文献
18.
19.
Song J Zhang XQ Ahlers BA Carl LL Wang J Rothblum LI Stahl RC Mounsey JP Tucker AL Moorman JR Cheung JY 《American journal of physiology. Heart and circulatory physiology》2005,288(5):H2342-H2354
Overexpression of phospholemman (PLM) in normal adult rat cardiac myocytes altered contractile function and cytosolic Ca2+ concentration ([Ca2+]i) homeostasis and inhibited Na+/Ca2+ exchanger (NCX1). In addition, PLM coimmunoprecipitated and colocalized with NCX1 in cardiac myocyte lysates. In this study, we evaluated whether the cytoplasmic domain of PLM is crucial in mediating its effects on contractility, [Ca2+]i transients, and NCX1 activity. Canine PLM or its derived mutants were overexpressed in adult rat myocytes by adenovirus-mediated gene transfer. Confocal immunofluorescence images using canine-specific PLM antibodies demonstrated that the exogenous PLM or its mutants were correctly targeted to sarcolemma, t-tubules, and intercalated discs, with little to none detected in intracellular compartments. Overexpression of canine PLM or its mutants did not affect expression of NCX1, sarco(endo)plasmic reticulum Ca(2+)-ATPase, Na(+)-K(+)-ATPase, and calsequestrin in adult rat myocytes. A COOH-terminal deletion mutant in which all four potential phosphorylation sites (Ser62, Ser63, Ser68, and Thr69) were deleted, a partial COOH-terminal deletion mutant in which Ser68 and Thr69 were deleted, and a mutant in which all four potential phosphorylation sites were changed to alanine all lost wild-type PLM's ability to modulate cardiac myocyte contractility. These observations suggest the importance of Ser68 or Thr69 in mediating PLM's effect on cardiac contractility. Focusing on Ser68, the Ser68 to Glu mutant was fully effective, the Ser63 to Ala (leaving Ser68 intact) mutant was partially effective, and the Ser68 to Ala mutant was completely ineffective in modulating cardiac contractility, [Ca2+]i transients, and NCX1 currents. Both the Ser63 to Ala and Ser68 to Ala mutants, as well as PLM, were able to coimmunoprecipitate NCX1. It is known that Ser68 in PLM is phosphorylated by both protein kinases A and C. We conclude that regulation of cardiac contractility, [Ca2+]i transients, and NCX1 activity by PLM is critically dependent on Ser68. We suggest that PLM phosphorylation at Ser68 may be involved in cAMP- and/or protein kinase C-dependent regulation of cardiac contractility. 相似文献
20.
Akcakanat A Singh G Hung MC Meric-Bernstam F 《Biochemical and biophysical research communications》2007,362(2):330-333
The mammalian target of rapamycin (mTOR) is a central regulator of cell growth. mTOR exists in two functional complexes, mTORC1 and mTORC2. mTORC1 is rapamycin-sensitive, and results in phosphorylation of 4E-BP1 and S6K1. mTORC2 is proposed to regulate Akt Ser473 phosphorylation and be rapamycin-insensitive. mTORC2 consists of mTOR, mLST8, sin1, Protor/PRR5, and the rapamycin insensitive companion of mTOR (rictor). Here, we show that rapamycin regulates the phosphorylation of rictor. Rapamycin-mediated rictor dephosphorylation is time and concentration dependent, and occurs at physiologically relevant rapamycin concentrations. siRNA knockdown of mTOR also leads to rictor dephosphorylation, suggesting that rictor phosphorylation is mediated by mTOR or one of its downstream targets. Rictor phosphorylation induced by serum, insulin and insulin-like growth factor is blocked by rapamycin. Rictor dephosphorylation is not associated with dephosphorylation of Akt Ser473. Further work is needed to better characterize the mechanism of rictor regulation and its role in rapamycin-mediated growth inhibition. 相似文献