Summary
Research on PI 3-Kinase (PI3K) is undergoing significant shifts in emphasis. Questions that have been dormant for some time are coming to the forefront, such as the relationship of PTEN to PI3K and the role of AKT in PI3K-driven oncogenesis. Two non-alpha isoforms of Class I PI3K are now established as important determinants in cancer: p110β and p110δ. The oncogenic activities of p110β include a non-catalytic function, a finding that will have immediate consequences for drug development.
Introduction
The PI 3-Kinase (PI3K) field has entered a phase of rapid and dynamic development. Although the basics remain unchanged, there are significant shifts in accents and emphasis. This is particularly true of Class I PI3K which has great significance for cancer and which will be the subject of this review. Among the questions that have recently come under scrutiny is the role of AKT (murine thymoma viral oncoprotein homolog) in the oncogenic signals from PI3K and the relationship between loss of PTEN (phosphatase and tensin homolog) and activation of PI3K. The non-alpha isoforms of Class I p110 are shedding their tentative and subordinate roles in oncogenesis and are emerging as important factors in cancer. In this paper, we will discuss questions that are raised by these recent developments.
PI3K was initially linked to cancer in studies of oncogenic viruses. The middle T antigen of polyoma virus, the Src oncoprotein of Rous sarcoma virus and the Ros oncoprotein of the avian sarcoma virus UR2 are associated with PI3K activity [1–3]. More direct evidence for the oncogenic potential of PI3K comes from avian sarcoma virus 16 which carries a homolog of the PIK3CA gene, coding for p110α, the catalytic subunit of PI3K, as its tumorigenic determinant [4]. In human cancer, deregulation of the PI3K signaling pathway has been recorded with increasing frequency, caused by gain of function in receptor tyrosine kinases, amplification of PIK3CA, activation of the serine-threonine kinase AKT or loss of function of the tumor suppressor phosphatase PTEN that is the catalytic antagonist of PI3K [5–8]. But it was the discovery of cancer-specific mutations in PIK3CA that moved PI3K into the limelight [9]. These mutations confer a gain of function as measured by enzymatic activity, constitutive downstream signaling and oncogenic potential [10–15]. About 80 % of the mutations occur in three hot spots in the gene, each represented by a single nucleotide substitution. The existence of these hot spots strongly suggests that the mutations provide a replicative advantage to the cell which is in accord with the gain of function detected by diverse assays of activity [9]. The mutant p110α proteins would appear as ideal therapeutic targets: they are restricted to cancer cells and, as enzymes, are readily controllable by small-molecule compounds, but mutant-specific inhibitors have not yet been generated [16].
Mutants and mechanisms
The mutant p110α proteins have raised the question of the molecular mechanisms that are responsible for the gain of function. Definitive answers to this question must await specific structural information on the mutants. Genetic experiments suggest the existence of several such mechanisms. Thus, combining kinase domain and helical domain hot spot mutations in the same molecule has a strong synergistic effect on signaling and oncogenicity. Kinase and helical domain mutations also differ in their requirements for interaction with RAS (rat sarcoma virus oncoprotein homolog) and with the PI3K regulatory subunit p85. The helical domain mutations of PIK3CA depend on interaction with RAS for full oncogenic activity but are independent of binding to the regulatory subunit p85. The kinase domain mutation shows the opposite requirements. It is oncogenic in the absence of RAS binding but fails to transform cells if the interaction with p85 is disabled [17]. In addition to the frequent hot spot mutations, almost 100 rare mutations have been identified in PIK3CA (Catalogue of somatic mutations in cancer, Wellcome Trust Sanger Institute; URL: http://www.sanger.ac.uk/genetics/CGP/cosmic/). A study of 15 of these rare mutations revealed varying degrees of increased function and of oncogenicity in all but one [18]. Most cancer-specific mutations in PIK3CA, regardless of their incidence may therefore contribute to the oncogenic phenotype of the cancer cell.
Cancer-specific mutations map over the entire coding sequence of PIK3CA, with the exception of the RAS-binding domain. The exceedingly broad distribution of mutations and the fact that many are located on the surface of the protein and affect electrostatic charge suggest that interactions with other proteins are involved. Changes in the binding to regulatory proteins may be the critical mediators of the gain of function in p110α mutants [19]. A well documented example for an altered interaction are the hot spot mutants located in the helical domain of p110α. They relieve an inhibitory interaction between that domain and the N-terminal SH2 domain of p85 [20]. The absence of mutations in the RAS-binding domain may indicate an importance of that domain not only in RAS binding [21], but also in the structural integrity of the protein.
Mutants of a different kind have been investigated by Zunder and coworkers [22]. Using a battery of PI3K inhibitors and an efficient and rapid yeast-based screen, they generated and analyzed p110α mutations that confer resistance to specific inhibitors. PI3K inhibitors, like protein kinase inhibitors, bind to the ATP affinity pocket. Surprisingly, most single-amino acid substitutions at this site in p110α lead to loss of activity, including the “gate-keeper” mutation that ranks prominently in drug-resistant mutants of protein kinases. In the ATP-binding cavity of p110α, only a single residue (I 800) was capable of inducing resistance when mutated.
PI3K, PTEN and AKT: Questions of correlations and connections
Figure 1 presents basic elements of PI3K signaling from upstream input by activated receptor tyrosine kinases or G-protein-coupled receptors to one of the major downstream targets, the TOR (target of rapamycin) kinase. Although didactically useful, such simplistic renderings could inadvertently lead to incorrect assumptions. For instance, on paper, a loss of function in PTEN is equivalent to a gain of function in PI3K, as both lead to increased levels of PIP3 which are regarded as the determining factor in PI3K signaling. This view is almost certainly incorrect. PI3K and PTEN both affect numerous cellular activities, but their target spectra are only partially overlapping. The effect of varied cellular localization on PI3K and PTEN functions, nonenzymatic scaffolding activities of PTEN and the differential effect of PTEN loss on p110 isoforms are currently active topics of research and discussion [23–27]. A recent analysis of human cancers at various sites strongly suggests that PIK3CA gain-of-function mutations and PTEN loss are not equivalent [8]. Thus, mutations in PIK3CA and loss of PTEN often coexist in human cancers. Therefore, they must be independently selected for, and make distinct, non-redundant contributions to the oncogenic phenotype. In contrast, double mutations in PIK3CA that affect the same enzymatic and signaling activity are very rare. Another problematic point in the canonical PI3K signaling scheme is AKT. It is widely assumed that AKT is an obligatory component of the oncogenic signal from PI3K to downstream targets. However, there are observations that do not fit this assumption, suggesting that the link between PI3K and AKT can be uncoupled. For instance, there are p110α mutations that induce oncogenic transformation in the absence of detectable phosphorylation of AKT, and, vice versa, p110α mutants exist that fail to transform despite robust AKT phosphorylation (Figure 2) [17,18]. Furthermore, mutants of p110α in general differ widely in their ability to induce phosphorylation of AKT at T308 and S473, and these differences are not correlated with oncogenic activity. These unexplained observations make it clear that the role of AKT in PI3K signaling needs to be defined more precisely.
Figure 1.
The pathway from PI3K to TOR. Recent publications have focused on the PI3K-PTEN interactions and on the role of AKT in oncogenic, PI3K-driven signaling. Loss of PTEN has differential effects on PI3K isoforms. The lack of correlation between oncogenic activity of PI3K and signaling through AKT suggests new crosstalks and alternative pathways. PIP2, phosphoinositide 4,5 bisphosphate; PIP3, phosphoinositide 3,4,5 trisphosphate; PDK1, phosphoinositide-dependent kinase; TSC1/TSC2, tuberous sclerosis complex; RHEB, RAS homolog enriched in brain.
Figure 2.
PI3K and AKT uncoupled. The figure shows examples of non-correlation between PI3K activity and phosphorylation of AKT [15,18].
The non-alpha isoforms of Class I p110: emerging roles in cancer
Class I PI3K contains four p110 isoforms, α, β, γ and δ. The association between p110α and cancer is well established and has been greatly strengthened by the occurrence of gain-of-function p110α mutations in human cancer [9]. The relationship of the non-alpha isoforms to cancer and their possible role as oncogenes has been more tenuous, but recent discoveries have changed that situation. A surprising observation was made with the four p110 isoforms overexpressed in avian fibroblasts. Whereas wild-type p110α failed to induce oncogenic transformation, all three non-alpha isoforms proved oncogenic in this cell system [28]. Oncogenic transformation has also been obtained with p110β and p110γ in mouse 10T1/2 cells (Ueno and Vogt, unpublished observation). A more detailed investigation of the p110 isoforms in avian cells uncovered differences in constitutive signaling, requirement for RAS interaction, and sensitivity to inhibitors of the MAP (mitogen-activated protein) kinase pathway. In these cells, only p110δ signals constitutively through AKT; p110δ is also exceptional in that its oncogenic activity is resistant to inhibitors of the MAP kinase pathway and appears not to require binding to RAS. In contrast, p110α, β, and γ lose oncogenic activity when RAS binding is disabled; p110β and p110γ are also highly sensitive to inhibitors of MAP kinase signaling. The loss of function induced in p110β and p110γ by a mutation in the RAS binding domain can be restored by a myristylation signal, suggesting a role of RAS in membrane recruitment [29].
The p110β isoform has now been firmly linked to oncogenesis by several groundbreaking papers published this year (Figure 3). The study of Jia et al. Uses mice with a conditional knockout of the PIK3CB, the gene encoding p110β [30]. The results define a new role of p110β in insulin signaling and show that both kinase-active and kinase-inactive forms of p110β have important functions in cell growth and trafficking. Of particular interest and importance is the observation that cultures of mouse embryo fibroblasts with a PIK3CB knockout cannot be transformed by constitutively active RAS or EGFR. Sensitivity to oncogenic transformation is restored by introducing wild-type p110β into these cells and, amazingly, sensitivity to transformation is also partially re-established by a kinase-inactive mutant of p110β. On the organismic level, Jia et al. found that ablation of p110β blocks prostate tumorigenesis mediated by loss of PTEN. Surprisingly, a prostate-specific knockout of p110α in these mice did not affect tumor formation. With these studies, p110β becomes a therapeutic target in cancer. However, the fact that kinase-inactive p110β can perform an essential role in oncogenesis will require new strategies for drug development. Conventional kinase inhibitors affecting the enzymatic activity of p110β would probably still leave its kinase-independent functions intact. It will be essential to learn more about this scaffolding activity of p110β. The observations of Jia and coworkers on the murine prostate cancer model suggest a connection between loss of PTEN and signaling by p110β. This link is also documented by the investigations of Wee and colleagues [25]. In PTEN-negative human cancers, p110β, but not p110α is essential for signaling and for replication. In another important publication on p110β, Ciraolo and coworkers have investigated mice that carry the homozygous kinase-inactive K805R mutation [31]. Animals expressing high levels of p110β(K805R) go through transient growth retardation but survive to adulthood, suffering from mild defects in insulin signaling. In contrast, low expressor siblings die in utero. Embryonic fibroblasts with low p110β(K805R) expression show inhibition of growth, but cells with high expression of the mutant protein replicate normally, providing additional evidence for a kinase-independent function of p110β in cell growth. In an ERBB2-driven model of breast cancer, the K805R mutation of p110β has a significant protective effect, indicating a role for p110β in the development of these tumors. This connection between p110β and a receptor tyrosine kinase appears in conflict with solid evidence that identifies G-protein-coupled receptors as the exclusive upstream signaling components for p110β [32]. The contradiction could be resolved by postulating crosstalk between ERBB2 and G-protein-coupled receptors. Such crosstalk has indeed been found in certain cell types [33]. A less prominent development on p110 isoforms and cancer concerns p110δ. Unlike p110α and p110β, p110δ is not ubiquitously expressed and is restricted mainly to hematopoietic cells. It has not ranked high as a cancer target, but has been considered for immune disorders [34–37]. However, it has been known for some time that p110δ is overexpressed in acute myeloblastic leukemia and that these leukemia cells are sensitive to isoform-specific inhibitors of p110δ [38,39]. These findings have been confirmed and expanded, and a p110δ-specific inhibitor is currently in phase I clinical trial for non-Hodgkins lymphoma, acute myeloblastic leukemia and chronic lymphoblastic leukemia (ClinicalTrials.gov, identifier NCT0070528).
Figure 3.
Involvement of p110β in oncogenesis [30,31]. A. Cultures of mouse embryo fibroblasts (MEF) lacking p110β cannot be transformed by activated RAS. Re-expression of p110β in these cells makes the cultures permissive for RAS-induced transformation. Surprisingly, MEF cultures expressing the catalytically inactive K805R mutant of p110β can also be transformed by RAS, albeit with lower efficiency. B. In a PTEN¯-driven model of prostate cancer, ablation of p110β, but not of p110α prevents tumor formation. In an ERBB2-driven model of breast cancer, substitution of wildtype p110β with the kinase-inactive K805R mutant has a tumor-protective effect.
Conclusions
We still know far too little about the direct and indirect interactions between PTEN and PI3K and their extensive signaling networks. Recent publications have brought insights and focus to this problem [8,23–25,27,30]. They support the conclusion that loss of PTEN has isoform-specific consequences for PI3K, and these consequences may be cell type-specific. The entry of p110β and p110δ into the realm of cancer marks a milestone for the therapeutic potential of targeting these isoforms. At the same time, the bar for successful drug development is raised by the discovery of catalysis-independent oncogenic functions of p110β.
Catalytically active and inactive p110β in cell replication and oncogenesis.
Mice homozygous for the K805R kinase-inactive mutation of p110β show partial protection from tumorigenesis in an ERBB2-induced model of breast cancer [31]. In a prostate cancer model driven by loss of PTEN, ablation of p110β prevents tumor formation, whereas loss of p110α has no effect on tumorigenesis [30]. Loss of PTEN function generally leads to a dominance of p110β in signaling and regulation of growth. In PTEN¯ human cancer cells, knock-down of p110β, but not of p110α interferes with signaling and cell replication [25]. Mice with the K805R mutation in p110β can survive to adulthood, provided the expression of the catalytically inactive p110β is high. This observation documents non-enzymatic, dosage-dependent functions of p110β in development and growth [31]. In cell culture, ablation of p110β prevents oncogenic transformation by activated RAS and other oncoproteins. Re-expression of p110β in these cultures restores the transforming activity of RAS. The cell cultures also regain partial susceptibility to transformation if instead of the wild-type p110β the K805R mutation is added back onto the p110β¯ background [30].
Acknowledgment
Work of the authors is supported by grants from the National Cancer Institute and by the Stein Fund. This is manuscript number 19791 of The Scripps Research Institute.
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