Phosphatase and tensin homolog deleted on chromosome Ten Pten

The tumor suppressor, PTEN, is a dual phosphatase that has activity for both lipid and protein substrates. It is a gene that is lost in both heritable and spontaneous cancers where germline mutations cause autosomal dominant hamartoma tumor syndromes and where spontaneous missense mutations occur frequently in the central nervous system (20%), endometrial (39%), colorectal (9%), skin (17%), prostate (14%), and breast (6%) cancers [95]. Its role within the PI3K pathway serves to negatively regulate PI3K signalling. PTEN functions to remove phosphates in position 3' from phosphoinositides [93, 106, 107], therefore, returning PIP3 to PIP2 and terminating the PI3K signal. Monoallelic loss (loss of heterozygosity) and/or mutation of PTEN thus, leads to a hyperactive PI3K pathway to drastically impact tumor growth and disease severity. PTEN mutants that retain protein tyrosine phosphatase activity but lose the ability to dephosphorylate PIP3 are found in many tumours indicating that PTEN lipid phosphatase activity is required for tumour suppression.

PTEN is tightly regulated at the transcriptional level as well as by post translational modification, primarily through ubiquitylation. Incidentally, the levels of PTEN are controlled by PI3K itself, through the regulation of the transcription factor NF-kB, while, PPARp/5 agonists and TNFa repress PTEN expression [93, 108]. Furthermore, the activity of PTEN is also controlled by the PI3K pathway. In p85 conditional knockout mice, the loss of p85 resulted in PTEN activity, while loss of p1105 isoform regulated PTEN activity through a RhoA-ROCK-depedent signaling [93, 109]. Currently, NEDD4-1 is the first and only identified E3 ligase for PTEN [93, 110]. Similar to PTEN, NEDD4-1 is also regulated by the PI3K pathway, thus representing a positive feedback for PTEN degradation and PI3K activation [93, 111]. More often than not, heterozygous alterations of PTEN are most common in the initial steps of tumorigenesis. Surprisingly, complete PTEN deletion does not have pro-tumorigenic effect. For example actute PTEN loss within prostate cells leads to a strong p53 dependent senescence response that opposes cancer progression. Hence, it can be suggested that tumors may not select for a complete loss of function of PTEN during the initial states of tumorigenesis. For example, in CaP patients, approximately 70% of tumors have heterozygous alteration in PTEN at presentaiton and then lose the other allele at later stages [93].

The co-existence of both PIK3CA mutations and PTEN loss has been observed in various cancers. This suggests that these two genetic aberrations are not completely redundant and may have additional selective advantage [95]. Yuan and Cantley, (2008) postulate that PTEN and p110a exist in a negative feedback loop to regulate pathway activity, such that any alterations to these enzymes results in heightened oncogenic potency of the PI3K pathway.

The formation of PIP3 is the central initiating event which functions to recruit plekstrin homology (PH) domain containing proteins to the plasma membrane. Of relevance here, is AKT/PKB, as it is the critical mediator of signal tranduction events downstream the PI3K cascade. There are three members of the AKT family (AKT1, AKT2, and AKT3) and they are broadly expressed to have some isoform specific features [87]. AKT1 is the major isoform implicated in cancers, whereas AKT2 is more so involved in insulin signaling and glucose transport. AKT3 on the other hand has well known features and functions, however is thought to play a specific role in brain tissue [86, 112].

The AKT gene encodes a serine/threonine kinase with an amino-terminal PH domain, a central catalytic domain, and a carboxyl-terminal regulatory domain. The regulation of AKT function is two- fold, requiring its translocation to the plasma membrane and its sequential phosphor-ylation at Threonine 308 (T308) and Serine 473 (S473). Within unstimulated cells, AKT is constitutively phosphorylated at S124 and T450. Upon PIP3 formation, there is direct interaction of AKT to PIP3 via is PH domain. Here, PDK1 phosphorylates AKT on T308. The phos-phorylation of T308 is a priming event to mediate the phosphorylation of S473 by PDK2, now thought to be the mammalian target of rapamycin complex 2 (mTORC2). This secondary event is necessary for maximal activation of the kinase, increasing AKT activity 10-fold [86, 113,

114]. Once activated AKT has many substrates within the cytoplasm and nucleus, including those that regulate apoptosis, proliferation, and protein translation. Although the activation of AKT has been well established, there is little known regarding the dephosphorylation of AKT as no AKT specific phosphatase has been identified. However heat-shock protein 90 (HSP90) has been demonstrated to protect AKT from dephosphorylation by the ubiquitous phosphatase, PP2A.

The activation of AKT regulates many cellular processes including cell proliferation and survival, cell size and glucose homeostasis, metabolism, angiogenesis, and tissue invasion [86, 93]. Amplification and mutations of AKT have been reported for pancreas, ovarian, head and neck and breast cancers. This includes a recently identified missense mutation to the PH domain of AKT1 (E17K) [95]. Such a mutation resulted in constitutive association of AKT with the plasma membrane and its prolonged activation. The biological effects of AKT activation relevant to cancer is primarily associated with cell survival, proliferation and growth. First, AKT functions as an anti-apoptotic response to various stimuli. This is through a series of phosphorylation and inhibition events of key pro-apoptotic proteins including, BAD, MDM2 and members of the Forkhead family of proteins.

BAD is a member Bcl-2 family of pro-apoptotic protein where these members form non-function hetero-dimer complexes with the survival factor BCL-Xl [87]. Once AKT phosphor-ylates BAD on S136, it prevents the interaction of BAD with BLC-XL to restore the anti-apoptotic function of BCL-XL [86, 115]. AKT also phosphorylates the pro-death enzyme, caspase 9, and inhibits its catalytic activity; this is in addition to preventing the nuclear localization of the Forkhead family of transcription factor, FKHR which transcriptionally inhibits the expression of pro-apoptotic proteins, BIM and FAS ligand. Alternatively, an indirect mechanism of AKT regulation of apoptosis is mediated by the NF-kB pathway and p53. Specifically, phosphorylation of and hence, the activation of IkB kinase (IkK) results in the degradation of NF-kB inhibitor, IkB, causing the nuclear translocation of NF-kB and the expression of anti-apoptotic genes. The pro-apoptotic effects of p53 tumour suppressor protein are mediated by AKT phosphorylation of the p53 binding protein MDM2. MDM2 is a negative regulator of p53 function as it targets p53 for ubiquitin mediated proteosomal degradation through its E3 ubiquitin ligase activity. The phosphorylation of MDM2 increases the efficiency by which MDM2 translocates to the nucleus thereby enhancing p53 degradation.

The proliferative effects of AKT activation can be attributed to its role by inactivating the cell cycle inhibitor p27 and p21, and, by inhibiting the enzyme, glycogen synthase kinase (GSK) 3p at its Serine 9 phosphoryaltion site. The regulation of cell cycle progression is through cyclin-cyclin-dependent kinase (CDK) complexes and CDK inhibitors (CKI). p27and p21 are CKIs that become phosphorylated by AKT and through indirect mechanisms, AKT phosphorylation can modulate the expression of CKIs as well as their activities. Phosphorylation of p27 renders it inactive and promotes cell cycle entry. Additionally, phosphorylation of the transcription factor, FOXO3A, by AKT causes the nuclear expulsion of the transcription factor, and therefore decreases the expression of p27 [116]. Alongside CKIs, cyclin D1 levels are important for G1/S phase transition through the cell cycle. AKT has an important role in preventing cyclin D1 degradation by inhibiting the cyclin D1 kinase, GSK3p. This prevents the phosphorylation of cyclin D1 thereby increasing its levels to enable cell cycle progression. Interestingly, cyclin D1 expression is also tightly controlled by FOXO3A. Upon AKT phosphorylation of FOXO, its exclusion from the nucleus increases cyclin D1 expression. In effect, FOXO3A is considered a transcriptional repressor for this gene.

The significance of AKT in cancer progression is further heightened by its role in cell growth and metabolism. In highly proliferating tumor cells, there is rapid synthesis of macromolecules to meet the biosynthetic demands required by the cell. Incidently, AKT is one of the main regulators of protein translation and ribosome biogenesis [93], facilitating the means for cell growth. This is primarily achieved through the serine/threonine kinase, mammalian target of rapamycin (mTOR or FRAP1) Complex 1, which is composed of the protein kinase mTOR and a series of interactors. This complex serves as a molecular sensor of nutrient availability and in effect, modulates protein synthesis. It is unlikely that the PI3K/AKT pathway is the sole simulator of mTOR activity. Nonetheless, AKT's phosphorylation of two independent substrates of this complex contributes to the oncogenic phenotype. Specifically, AKT phos-phorylates and inactivates the GTPase-activating protein (GAP) Tuberous Sclerosis Complex (TSC) 2 which forms a complex with TSC1 to inhibit the GTPase, Ras-homolog enriched in brain (Rheb). Rheb then directly interacts with mTOR and activates mTORC1 through the inhibition of FKBP38, the negative regulator of mTORC1. Alternatively, the phosphorylation and inhibition of another negative regulator of mTORC1, PRAS40 (proline-rich AKT substrate of 40kDa), enhances the activity of mTORC1 through its competition with GTPase Rheb. Altogether then, AKT promotes the activation of mTORC1 which initiates the translational machinery to produce ribosomes and increase the rate of protein synthesis. REFS

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