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Carcinogenesis Advance Access originally published online on March 6, 2007
Carcinogenesis 2007 28(7):1379-1386; doi:10.1093/carcin/bgm052
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

PTEN, more than the AKT pathway

Carmen Blanco-Aparicio, Oliver Renner, Juan F.M. Leal and Amancio Carnero*

Experimental Therapeutics Programme, Spanish National Cancer Centre (CNIO), C/Melchor Fernandez Almagro 3, 28029 Madrid, Spain

* To whom correspondence should be addressed. Tel: +34 91 732 8021; Fax: +34 91 732 8051; Email: acarnero{at}cnio.es


   Abstract
Top
 Abstract
The PTEN/AKT pathway
 PTEN/AKT genetics
 AKT-independent pathways
 Concluding remarks
 References
 
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/phosphatidylinositol 3-kinase (PI3K)/AKT constitute an important pathway regulating the signaling of multiple biological processes such as apoptosis, metabolism, cell proliferation and cell growth. PTEN is a dual protein/lipid phosphatase and its main substrate phosphatidyl-inositol 3,4,5 triphosphate (PIP3) is the product of PI3K. Increase in PIP3 recruits AKT to the membrane where is activated by other kinases also dependent on PIP3. Many components of this pathway have been described as causal forces in cancer. PTEN activity is lost by mutations, deletions or promoter methylation silencing at high frequency in many primary and metastatic human cancers. Germ line mutations of PTEN are found in several familial cancer predisposition syndromes. Recently, many activating mutations in the PI3KCA gene (coding for the p110{alpha} catalytic subunit of PI3K) have been described in human tumors. Activation of PI3K and AKT are reported to occur in breast, ovarian, pancreatic, esophageal and other cancers. Genetically modified mice confirm these PTEN activities. Tissue-specific deletions of PTEN usually provoke cancer. Moreover, an absence of PTEN cooperates with an absence of p53 to promote cancer. However, we have observed very different results with the expression of activated versions of AKT in several tissues. Activated AKT transgenic lines do not develop tumors in breast or prostate tissues and do not cooperate with an absence of p53. This data suggest that an AKT-independent mechanism contributes to PTEN tumorigenesis. Crosses with transgenic mice expressing possible PTEN targets indicate that neither cyclin D1 nor p53 are these AKT-independent targets. However, AKT is more than a passive bridge toward PTEN tumorigenesis, since its expression not only allows but also enforces and accelerates the tumorigenic process in combination with other oncogenes.

Abbreviations: DMBA, 7,12-dimethylbenz(a)anthracene; KO, knockout; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10; WT, wild type


   The PTEN/AKT pathway
Top
 Abstract
 The PTEN/AKT pathway
PTEN/AKT genetics
 AKT-independent pathways
 Concluding remarks
 References
 
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a dual lipid and protein phosphatase. Its primary target is the PIP3 (1), the direct product of the phosphatidylinositol 3-kinase (PI3K). Loss of PTEN function, either in murine embryonic stem cells or in human cancer cell lines, results in accumulation of PIP3 mimicking the effect of PI3K activation and triggering the activation of its downstream effectors, PDK1, AKT/PKB and Rac1/cdc42. PDK1 contains a C-terminal pleckstrin homology domain, which binds the membrane-bound PIP3 triggering PDK1 activation. Activated PDK1 phosphorylates AKT at thr308 activating its serine–threonine kinase activity (100-fold over the basal). Once phosphorylated in T308, further activation occurs by PDK2 (the complex rictor–mTOR or DNA-PK) by phosphorylation at S473. AKT activation stimulates cell cycle progression, survival, metabolism and migration through phosphorylation of many physiological substrates (2–6). AKT is a serine–threonine kinase downstream of PTEN/PI3K that has three family members: AKT1, AKT2 and AKT3, which are encoded by three different genes (7). They are ubiquitously expressed, but their levels are variable depending upon the tissue type. The N-terminus contains a pleckstrin homology domain that binds phospholipids, a central kinase domain, and a regulatory serine phosphorylation site in the C-terminus. AKT activity is regulated by PI3K, which recruits AKT to the cell membrane, permitting its activation by PDK1 (4). AKT is phosphorylated and activated by growth factors, including insulin and insulin growth factor-1. AKT also plays an important role in promoting cell survival (4,5,7). A number of substrates have been identified, including the pro-apoptotic proteins BAD and pro-caspase 9. Other substrates include the forkhead transcription factors, chiefly AFX, FKHR and FKHRL1, resulting in the inhibition of their transcriptional activities (8,9). The forkhead family of transcription factors plays a pivotal role in the regulation of cell proliferation and differentiation. It has been shown that AKT phosphorylates FKHR1, an event that prevents FKHR1 entry into the nucleus. A potential link between AKT activation and differentiation has also been implied (9). Localization to the membrane seems to be critical for AKT activation. Modifications that target AKT to the membrane, such as the gag sequence found in v-AKT or fusion of a myristoylation sequence from Src-like kinases to the N-terminus of AKT results in the constitutive activation of the kinase (10–12). Activation of AKT results in the suppression of apoptosis induced by a number of stimuli including growth factor withdrawal, detachment of extracellular matrix, UV irradiation, cell cycle discordance and activation of FAS signaling (4,5,13). Hyperactivated AKT has been also shown to promote cell proliferation, possibly through down-regulation of the cyclin-dependent kinase inhibitor p27 as well as up-regulation and stabilization of cyclin D1 (14).

Different genetic approaches have been used to directly assess the role of AKT in PTEN null-induced phenotype. Deleting AKT1 reversed the cell survival phenotype in PTEN-null cells and reversed its growth advantage (15). Furthermore, deleting both alleles of AKT1 appears to have additional effects, and mutated cells were more sensitive to serum starvation-induced cell death. AKT1 knockout (KO) cells lose the ability to compete with wild-type (WT) or PTEN-null cells (15). Similarly, inactivation of AKT by dominant-negative mutants inhibits the survival advantage provided by activated class I PI3K (16). These and other results point out the essential role of AKT in the PTEN/PI3K pathway (17–21).

The PTEN/PI3K pathway is highly involved in cancer. PTEN activity is lost by mutations, deletions or promoter methylation silencing at high frequency in many primary and metastatic human cancers (6,22). Germ line mutations of PTEN are found in Cowden, Bannayan-Riley-Ruvalcaba and a Proteus-like syndromes, all familial cancer predisposition syndromes (23–26). Recently, many activating mutations have been described in the PI3KCA gene (coding for the p110{alpha} catalytic subunit of PI3K) to be present in human tumors (22,27). Activation of PI3K and AKT are reported to occur in breast (28–30), ovarian (29,31,32), pancreatic (33), esophageal (34) and thyroid cancer (35) and other cancers (22,36).


   PTEN/AKT genetics
Top
 Abstract
 The PTEN/AKT pathway
 PTEN/AKT genetics
AKT-independent pathways
 Concluding remarks
 References
 
Transgenic studies showed that although knockout of PTEN is embryonically lethal, heterozygous mice develop tumor in several organs (37–41). Moreover, heterozygous PTEN mice crossed with MMTV-wnt1 transgenic mice develop mammary tumors earlier in life than parental strains (42). In conditional models, PTEN loss resulted in the generation of tissue-specific tumors. Elimination of PTEN specifically in the mammary gland by MMTV-Cre originates excessive side branching, accelerated ductal extension and mammary tumors with metastatic properties (43,44). Similar tumorigenic properties have been observed in other tissues after PTEN conditional excision (45–49). In these models, conditional PTEN depletion also resulted in developmental defects, highlighting the importance of PTEN to normal differentiation. In conditional epidermal knockouts, 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate chemical carcinogenesis elicited tumors that rapidly progressed to carcinoma (50) via mechanisms centered on failed apoptosis and increased mitogen-activated protein kinase activity, consistent with AKT activation in classic two-stage chemical carcinogenesis. However, DMBA/12-O-tetradecanoylphorbol-13-acetate chemical carcinogenesis using heterozygous PTEN KO mice (51) found that whereas papillomas exhibited H-ras activation, squamous cell carcinomas failed to exhibit any ras mutations, suggesting that mutually exclusive pathways existed between H-ras-mediated and PTEN-mediated carcinogenesis.

However, despite its proposed relevance in the PTEN pathway, no equivalent results have been found with activated AKT transgenes. At least four independent groups have generated transgenic mice expressing constitutively active AKT in the mammary gland under the control of MMTV promoter (52–55) (Table I). Activation of the AKT pathway led to involution defects, consistent with the phenotype in Pten conditional KO mice. However, no major differences could be observed in ductal growth and epithelial differentiation when comparing transgenic and control virgin females, despite the high expression levels of constitutively active form of AKT (53,55).


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  		Table I. Mouse models with PI3K pathway altered focus on mammary and prostate

 
Interestingly, comparing other mouse models (44,67), activated AKT accelerated erbB2 mammary tumors (60), but inhibited lung metastasis providing longer life expectancy in these mice. In a very interesting study, the mammary expression of polyoma middle T antigen provokes multifocal metastatic mammary tumors in mice (59). However, the same antigen depleted of its capability to activate PI3K only induces mammary hyperplasia with a high apoptotic index. The complementation of this defective polyoma middle T antigen ({Delta}PI3K) with active AKT recovered the accelerated tumorigenesis (53) (Table I).

The phenotypical differences between the PTEN and AKT mouse models could also be due to the involvement of a signaling pathway bifurcation between the PI3K/PTEN level and AKT. PI3K may control multiple pathways (PIP dependent or independent), including the AKT pathway. AKT is one of the proteins recruited to the membrane by PIP3 where it is activated by other PIP3-activated protein, PDK1. PDK1 has been termed the ‘master kinase’ (21,68) in that it has been shown to phosphorylate the critical residue in the activation loops of all AGC kinase family members including AKT1, 2 and 3 (69–74), SGKs (75,76), S6K (70,77), PKA (78), PKC{alpha} and PKCßII (79), PKC{delta} (80), PKC{zeta} (80,81), RSK (82) and protein kinase N (83,84). Many of them are related to cell proliferation or apoptosis. Bifurcation at PDK1 level is supported by hypomorphic PDK1 mice (85). Reduced levels of PDK1 expression in PTEN(+/–) mice markedly protects these animals from developing a wide range of tumors. Furthermore, other proteins might also been recruited and activated by PIP3 increase (5,86). The pleckstrin homology domain was the first phosphoinositide-binding domain identified. It contains the largest number of members and is associated with the formation of signaling complexes on the plasma membrane. Recent studies identified other novel phosphoinositide-binding domains (Fab1p, YOTB, Vps27p, EEA1, Phox homology and epsin N-terminal homology), thus extending the functional versatility of the pathway. Therefore, it is possible that PTEN loss phenotype be dependent on PIP3 increase where AKT is only a necessary but not sufficient step in PTEN/PI3K tumorigenesis (87). Then, constitutive activation of PI3K should reconstitute PTEN loss phenotype.

We have also generated mammary-specific activated PI3K by expressing myristoylated p110{alpha} under the MMTV promoter. We generated at least 10 different transgenic lines expressing different levels of active PI3K in the mammary gland and at least two lines with the transgene integrated in the Y chromosome and expressing high levels of PI3K in the prostate and other male reproductive organ tissues (Renner, O. et al., submitted for publication). We observed increased branching and ductal development similar to the observed in activated AKT models but in none of the lines we observed an increased tumoral phenotype in either mammary or prostatic models, at difference to the PTEN depletion in these organs.

This discrepancy could be due to insufficient levels of activated AKT. It has been determined the growth regulatory and signaling properties of the three most frequently observed PI3K mutations: E542K, E545K and H1047R and compared with membrane targeted PI3K (myrp110). Despite similar catalytic activity (88), myrp110 seems to have lower capability to activate AKT (89). Moreover, depending on the cellular system used, myrp110 also have lower oncogenic activity than the PI3K mutants (90,91). It is also possible that PIP3 subcellular localization represent an important factor in PTEN/PI3K physiological signaling (89).

Alternatively, PTEN may control multiple pathways, including the PI3K/AKT pathway. Therefore, can the observed phenotypes in Pten conditional deleted mammary gland be explained by activation of PI3K/AKT-independent pathway?


   AKT-independent pathways
Top
 Abstract
 The PTEN/AKT pathway
 PTEN/AKT genetics
 AKT-independent pathways
Concluding remarks
 References
 
Loss of PTEN function results in accumulation of activated AKT that plays a key role in PTEN-mediated tumorigenesis via multiple mechanisms including inhibition of apoptosis (5,13,86), over-expression of cyclin D (92,93) and interactions with MDM2 that lead to increased p53 degradation (94–96). Alternative mechanisms of PTEN-mediated tumorigenesis, possibly independent of AKT (97–100), show that PTEN directly associates with p53 increasing stability, protein levels and transcriptional activity. Similarly, PTEN regulates cell cycle arrest via protein phosphatase-dependent interaction with cyclin D. The oncogenic potential of PTEN is further highlighted by roles in integrin signaling and an ability to dephosphorylate focal adhesion kinase that reduce cell adhesion and enhance migration (101–103). The protein phosphatase activity of PTEN is necessary for its growth-suppressive effect. PTEN appears to inhibit cell cycle progression through the cooperation of its protein phosphatase activity, which leads to the down-regulation of cyclin D1, whereas its lipid phosphatase activity leads to up-regulation of p27 (92). PTEN also abrogates insulin-stimulated ETS2 activation independently of PI3K, probably through the protein phosphatase activity (97). ETS transform NIH3T3 allowing tumor formation in mice. Inhibition of ETS2 can inhibit ras-dependent transformation and abolish breast carcinoma cells anchorage independent growth and migration. ETS2 can also activate the cyclin D1 promoter.

Pten+/–;p53+/– double heterozygous mice on a 129/Balb/c genetic background show an onset of lymphoma development similar to that seen in p53–/– animals. p53 protein levels are dramatically reduced in Pten–/– cells due to PTEN-mediated stabilization of p53, which increases its half-life. Furthermore, ectopic expression of PTEN phosphatase-dead mutants also leads to a significant increase in p53 protein levels, and PTEN can stabilize p53, even in the absence of MDM2, suggesting that PTEN can regulate p53 levels in a phosphatase-independent and MDM2-independent manner. Moreover, PTEN physically associates with endogenous p53 and regulates the transcriptional activity of p53 by modulating its DNA binding (99).

To explore some of these AKT-independent mechanisms, we crossed three different MMTV-myrAKT transgenic lines with heterozygous p53(+/–) KO mice or MMTV-cyclin D1 transgenic mice. MyrAKT transgenic mice heterozygous for p53 showed higher levels of AKT phosphorylation and higher number of cells per duct and ducts with AKT activation in equivalent tissues in either females (mammary gland) or males (epididimis and prostate) (Figure 1). This observation proves the functional relationship described between p53 and PTEN in our model and corroborates previous findings (104). Reduced levels of p53 will down-regulate PTEN levels allowing activation of AKT. However, no phenotypic cooperation was observed. Survival curve for heterozygous p53(+/–) was identical in the presence of WT or activated AKT (Figure 2A). Only a slight increase in survival was observed in multiparous females expressing myrAKT transgene (Figure 2A). But even in this case, the median survival of multiparous p53(+/–);myrAKT is similar to virgin p53(+/–);myrAKT. It is possible that the metastatic protective effect of AKT might account for this increased survival in multiparous females. Furthermore, the analysis of tumors in these strains showed a very similar pattern (Table II). We have shown previously that the expression of myrAKT in the mammary ducts switches the type of mammary tumors induced by carcinogenic DMBA treatment toward tumors of epithelial origin (55). Therefore, we analyzed the origin of mammary tumors in p53(+/–);myrAKT strains (Table III). The distribution of tumor types is very similar among all genotypes. In addition, the low number of mammary tumors exhibiting tumors of an epithelial origin, only 10% of females, also argues against AKT and p53 cooperation in mammary tumorigenesis. This is in agreement with our previous work (54), in which we analyzed the status of p53 in mammary tumors induced by carcinogenic DMBA treatment in myrAKT transgenic mice and observed that p53 was WT in all cases.


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  		Table II. Phenotype of p53(+/–); mytAKT virgin colonies

 


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  		Table III. Percentage of mammary tumor type observed in virgin females

 


Figure 1
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  		Fig. 1. Expression of activated AKT in transgenic mice. (a) Immunohistochemical detection of phosphoS473 AKT in mammary glands (A, B and C) and epididymis (D, E and F) of 9-week-old nulliparous transgenic mice. Genotypes: (A and D) tg (myrAKT/+);p53(+/+), (B and E) tg(+/+);p53(–/+) and (C and F) tg (myrAKT/+);p53(–/+). (b) Low resolution of immunohistochemical detection of phosphoS473 AKT in mammary glands of 9-week-old nulliparous transgenic mice. Genotypes: (A) tg (myrAKT/+);p53(+/+) and (B) tg (myrAKT/+); p53(–/+).

 


Figure 2
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  		Fig. 2. Phenotype of myrAKT transgenic mice in a p53 heterozygous background. (A) Survival of three different myr-AKT transgenic mouse lines in p53 heterozygous background compared with parental p53(–/+) mice. (B) Phenotype of the mammary gland observed. Upper figures, representative red carmin and hematoxylin staining of different branching levels observed. Bottom table, quantification of branching observed in nulliparous and multiparous transgenic mice. Dots represent each mammary gland analyzed (one per individual) and lines represent the average.

 
In myrAKT transgenic mice, we have found that activated AKT might enhance some pre-neoplastic lesions in the mammary glands. Therefore, we have measured whether loss of p53 and AKT cooperated in the generation of these lesions. Macroscopically, we categorized the lesions into four types according to branching and feather-like phenotype (Figure 2B). We measured the appearance of all these phenotypes in the females of the different lines and averaged the observations (Figure 2B). The hemizygosity of p53 increased branching compared with WT mice, but showed the same phenotype independent of the presence of activated AKT. Similar observations were made in multiparous females (Figure 2B).

Therefore, our data indicate that p53 does not cooperate with AKT. Since it has been shown that p53 cooperates with PTEN loss and might be an essential bottleneck in PTEN loss-induced development of mammary tumors, our data suggest that these reported PTEN effects are not mediated through AKT. Therefore, PTEN loss might signal through another molecule cooperating with p53 in a lipid phosphatase-independent manner.

Cyclin D1 could be this molecule. To explore this possibility, we crossed MMTV-myrAKT with MMTV-cyclin D1 transgenes. MMTV-cyclin D1 produce low-penetrance mammary tumors (65). However, the B6 background is more resistant to tumor formation (105). Thus, we crossed myrAKT and cyclin D1 transgenic lines both in a B6 background and analyzed the possible cooperation between both molecules. The survival of CyclinD1 transgenic mice either with WT or activated AKT was similar in both males and females (Figure 3A) and tumors and pre-neoplasic lesions were also similar (Figure 3B), indicating absence of cooperation between AKT and CylinD1. The same negative effect in cooperation was observed when we crossed MMTV-myrAKT transgenes with heterozygous p27kip1 KO mice (data not shown).


Figure 3
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  		Fig. 3. Phenotype of myrAKT transgenic mice in a MMTV cyclinD1 transgenic background. (A) Survival of three different myr-AKT transgenic mouse lines in p53 heterozygous background compared with parental MMTV cyclinD1 transgenic mice. (B) Phenotype of the mammary gland observed. Upper figures: representative red carmin and hematoxylin staining of different branching levels observed. Bottom table: quantification of branching observed in nulliparous and multiparous transgenic mice. Dots represent each mammary gland analyzed (one per individual) and lines represent the average.

 
These data argue in favor that AKT might be necessary but not sufficient to trigger PTEN-dependent tumorigenesis (87) and that other signal independent from p53 and cyclinD1 is necessary in this task.

PTEN contains a sequence motif that is highly conserved in the members of the protein tyrosine phosphatase family. PTEN has been shown to possess phosphatase activity on phosphotyrosyl and phosphothreonyl-containing substrates (106–108) in vitro and on phosphatidylinositol (3,4,5) trisphosphate, a product of PI3K, both in vitro and in vivo (1,108–110). The fact that naturally occurring mutations in the PTEN phosphatase domain (such as PTEN-C124S and PTEN-G129E mutants) are tumor causing indicates that the effects of PTEN's phosphatase-independent activity in tumorigenesis may be more tissue specific or associated with a more aggressive phenotype upon loss of PTEN function. However, our data argue strongly that phosphatase-independent mechanisms are an important part of PTEN's biological functions. Notably, activation of AKT alone in transgenic mice cannot account for all the phenotypes related to PTEN loss (Table I). In Drosophila, phenotypes caused by dPTEN mutation are not completely covered by Dp110 or insulin-signaling mutants (111), suggesting PTEN may have a broader role than only antagonizing PIP3. Similarly, mutating the putative PIP2 motif in the N-terminal region of PTEN led to loss of PTEN membrane association and failure to rescue the PTEN-null phenotype in a chemoattractive response in Dictyostelium discoideum (112).

Inhibition of AKT can prolong the lifespan of primary cultured human endothelial cells whereas constitutive activation of AKT can foster senescence-like growth arrest via a p53/p21-dependent pathway (113), and inhibition of FOXO3a transcription in keratinocytes (114). AKT-induced growth arrest was inhibited by a mutated forkhead transcription factor that was resistant to AKT-mediated phosphorylation. Inducible activation of AKT results in growth arrest and a senescent phenotype in normal primary human epithelial cells. Hence, activation of AKT in primary cells may represent an anti-tumorigenic effect. However, in AKT-activated transgenic models, enforced AKT activation does not decrease tumorigenesis. In fact, it has been shown to accelerate primary mammary tumor development of Poly M T and erbB2 although metastasis was found to be reduced. In this context, it was also proposed that p53 was the effector of AKT-induced senescence (16,92). Therefore, if p53-mediated AKT-induced senescence was the limiting factor inhibiting AKT tumorigenesis, myrAKT should cooperate with p53(+/–) mice. However, we have shown this does not occur, indicating that AKT-induced senescence is not the only physiological mechanism uncoupling PTEN and AKT responses.

Despite its well-defined role at the plasma membrane, PTEN is found in the nucleus (115,116). Nuclear localization of PTEN may contribute to its tumor suppressor activity in several ways. Given that many components of the PI3K pathway are also found in the nucleus (117), it is possible that PTEN is a nuclear PIP3 phosphatase. However, a recent study suggests that nuclear PTEN does not dephosphorylate the nuclear pool of PIP3 (118). Other studies have implicated the protein phosphatase functions of nuclear PTEN down-regulating mitogen-activated protein kinase pathway, as well as cyclin D1, and inducing G1 cell cycle arrest. The regulation of p53 activity and stability by direct protein–protein interaction also occurs within the nucleus (100,119).

Recently, other tumor suppressor activity of nuclear PTEN has been reported occurring independently of AKT regulation, PTEN-null MEFs contain an increased number of chromosomal abnormalities (120). Although it was known that PTEN loss increased genomic instability by causing increased AKT-mediated sequestration of Chk1 and compromising DNA damage response, the nuclear PTEN co-localized with centromeres, bound to Cenp-C, which is required for proper kinetochore assembly and for the metaphase to anaphase transition. C-terminus but not the phosphatase domain of PTEN was required for this function (120). The chromosomal aberrations observed suggest a potential defect in the DNA damage checkpoint. Furthermore, PTEN was found to be bound to the Rad51 promoter suggesting a more direct impact of PTEN on transcription regulation (120). Although do not activate directly the transcription of Rad51, PTEN enhanced E2F-mediated transactivation. Other studies have also shown interactions of PTEN with PCAF and p300 transcriptional co-activators that function as histone acetyltransferases (100,121).


   Concluding remarks
Top
 Abstract
 The PTEN/AKT pathway
 PTEN/AKT genetics
 AKT-independent pathways
 Concluding remarks
References
 
AKT is necessary but not sufficient to trigger PTEN loss-dependent tumorigenesis (87). However, AKT is far from being only a passive bridge toward transformation. In mouse models, AKT expression not only recovers oncogene tumorigenesis but also enhances the aggressiveness of tumors. In PolyMT transgenic mice, multifocal mammary tumors occur and this phenotype is lost when PolyMT lacks the ability to bind PI3K. In double PolyMT {Delta}PI3K and active AKT transgenic mice, an accelerated mammary tumorigenesis was observed (53). The same positive cooperation was observed with other oncogenes such as MMTV-erbB2 (60). Therefore, a positive cooperation between AKT and another PTEN targets is necessary to provide full transforming activity. If this is true, positive correlation between this second alteration and PI3K mutations would be expected to be found in human tumors. It will be very interesting to identify this secondary route and clarify the physiological mechanism of cooperation.


   Acknowledgments
 
This work has been funded by Spanish Ministry of Health (FIS-02/0126), Fundacion Mutua Madrileña and Spanish Ministry of Education and Science (SAF2005-00944).

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 The PTEN/AKT pathway
 PTEN/AKT genetics
 AKT-independent pathways
 Concluding remarks
 References
 

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Received December 29, 2006; revised February 28, 2007; accepted March 1, 2007.


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