Elsevier

Cellular Signalling

Volume 18, Issue 8, August 2006, Pages 1101-1107
Cellular Signalling

Review
Intranuclear 3′-phosphoinositide metabolism and Akt signaling: New mechanisms for tumorigenesis and protection against apoptosis?

https://doi.org/10.1016/j.cellsig.2006.01.011Get rights and content

Abstract

Lipid second messengers, particularly those derived from the polyphosphoinositide metabolism, play a pivotal role in multiple cell signaling networks. Phosphoinositide 3-kinase (PI3K) generate 3′-phosphorylated inositol lipids that are key players in a multitude of cell functions. One of the best characterized targets of PI3K lipid products is the serine/threonine protein kinase Akt (protein kinase B, PKB). Recent findings have implicated the PI3K/Akt pathway in tumorigenesis because it stimulates cell proliferation and suppresses apoptosis. However, it was thought that this signal transduction network would exert its carcinogenetic effects mainly by operating in the cytoplasm. Evidence accumulated over the past 15 years has highlighted the presence of an autonomous nuclear inositol lipid cycle, and strongly suggests that lipid molecules are important components of signaling pathways operating at the nuclear level. PI3K, its lipid product phosphatidylinositol (3,4,5) trisphosphate (PtdIns(3,4,5)P3), and Akt have been identified within the nucleus and recent data suggest that they counteract apoptosis also by operating in this cell compartment through a block of caspase-activated DNase and inhibition of chromatin condensation. In this review, we shall summarize the most updated and intriguing findings about nuclear PI3K/PtdIns(3,4,5)P3/Akt in relationship with tumorigenesis and suppression of apoptotic stimuli.

Introduction

The transfer of signals from the plasma membrane to the cell nucleus is an exceedingly complex multistep process which strongly depends, among other components, on phosphatidylinositol (PtdIns) lipid signaling molecules [1]. The bulk of inositol lipids reside in cell membranes where they are substrates for kinases, phosphatases, and phospholipases [2]. The lipid kinase PI3K has emerged as an important constituent of multiple signaling pathways being involved in the control of many critical cell responses [3], [4]. It synthesizes four species of non-canonical, 3′-phosphorylated inositides: PtdIns(3)P, PtdIns(3,4)P2, PtdIns(3,5)P2, and PtdIns(3,4,5)P3. Compelling evidence suggests that members of PI3K family can also be considered as oncogenes, because they control cell cycle progression, differentiation, survival, invasion and metastasis, and angiogenesis [5]. Several biological effects of PI3K are mediated through the activation of the downstream target Akt, a serine/threonine protein kinase, which belongs to the family of the AGC protein kinases [6].

Most of the research on inositide-dependent signal transduction pathways has focused on events that take place at the plasma membrane. However, phosphoinositides and their biosynthetic machinery are localized also in the nucleus [7], [8], [9]. The regulation of the nuclear inositol lipid pool is largely independent from that of the plasma membrane, suggesting that the nucleus constitutes a functionally distinct compartment for phosphoinositide metabolism [7], [8], [9]. 3′-phosphorylated inositides, PI3K, and Akt have been reported to be present in the nucleus [10]. In this article, we shall highlight the existing knowledge about the role played by these molecules in the nucleus in relationship with tumor development and anti-apoptotic signaling. However, it is firstly necessary to briefly review some general data about 3′-phosphorylated inositides, PI3K, and Akt.

Section snippets

3′-phosphorylated inositol lipids and PI3K

Resting mammalian cells contain significant levels of PtdIns(3)P, but hardly any of the other 3′-phosphorylated inositides. While the overall levels of PtdIns(3)P do almost not increase upon cell stimulation with agonists, the levels of the other 3′-phosphorylated inositides can rise sharply [11]. Since these lipids are not the target of any known phospholipases, they are metabolized by phosphatases that act on the inositol ring. PTEN (phosphatase and tensin homologue deleted on chromosome 10)

Akt

At present, three members of the Akt family have been identified and are referred to as Akt1, Akt2, and Akt3. Although they are products of different genes, they are highly related exhibiting more than 80% sequence homology [6], [17]. In response to a variety of stimuli (hormones, growth factors, cytokines), inactive (cytosolic) Akt is recruited to the plasma membrane by the products of PI3K, PtdIns(3,4)P2 and PtdIns(3,4,5)P3. Then, Akt is phosphorylated at threonine 308 (by a

Nuclear 3′-phosphorylated inositol lipids and class IA PI3Ks

The presence of these inositol lipids in the nuclear compartment has been demonstrated by means of different techniques (radioisotope labeling, immunocytochemistry) in a variety of cell types [10]. Consistently with the presence of 3′-phosphorylated inositol lipids, the nucleus possesses proteins that bind these lipids, such as a 43-kDa PtdIns(3,4,5)P3-binding protein containing one zinc finger motif and two pleckstrin homology domains [21]. The first report dealing with PI3K at the nuclear

The regulation of nuclear class IA PI3K activity

While control of cytoplasmic class IA PI3K is quite well defined [e.g. [15], [16], regulation of its nuclear counterpart has been obscure. A major breakthrough has been achieved in PC12 cells stimulated with NGF. By means of a yeast two-hybrid approach, Ye et al. [26] identified the protein PIKE (PhosphoInositide 3-Kinase Enhancer) as a novel physiological regulator of nuclear class IA PI3K. PIKE is a nuclear GTPase characterized by a PX domain and three proline-rich domains, which typically

Nuclear Akt

It is now clear that phosphorylated (active) Akt is present within the nucleus (see Fig. 1). Indeed, some of its substrates are resident within this organelle, such as the FoxO family of transcription factors [30] or the transcriptional coactivator p300 [31]. Either Akt1 or Akt2 have been reported to migrate into the nucleus in response to a variety of stimuli including serum, activation of B-lymphocytes, hypoglycemic coma, mitogenic stimulation with polypeptide growth factors such as

Nuclear PTEN

There are several reports which have addressed the issue of nuclear PTEN. Four, non-traditional, putative NLS motifs have been identified in PTEN. Mutations in each of the four NLS-like regions of PTEN did not alter entry into the nucleus. However, when mutations were combined, it was found that nuclear localization of PTEN was affected, thereby indicating that nuclear import requires two NLS-like motifs acting in concert. Double NLS mutants did not interact with the major vault protein (MVP),

Involvement of 3′-phosphorylated inositol lipid metabolism and Akt in NGF-dependent anti-apoptotic signaling of PC12 cells

PI3K/Akt pathway is by far the most important signaling network for cell survival [54]. Traditionally, anti-apoptotic signaling by PI3K/Akt has been thought to take place at the plasma membrane level and in the cytoplasm [55]. However, recent findings point to the likelihood that nuclear PI3K plays an essential role in promoting cell survival also through nuclear PtdIns(3,4,5)P3 synthesis.

The PC12 cell line was originally derived form rat pheochromocytoma and can be differentiated by means of

Anti-apoptotic function of nuclear Akt in cardiomyocytes

Apoptosis occurs in a wide variety of cardiovascular disorders and is now recognized as a fundamental process contributing to deterioration of cardiac function which characterizes heart failure. Akt targeting to the nucleus of cardiomyocytes did not result in morphological remodeling such as altered myofibril density or hypertrophy. Nuclear targeted Akt was as effective as myristolated-Akt in counteracting hypoxia-induced cell death of cardiomyocytes. Collectively, these findings suggested that

Conclusions

The significance of the existence of an autonomous inositol lipid metabolism is slowly beginning to take shape. Divecha et al. [80] originally hypothesized that the nuclear inositol lipid cycle might have evolved first to regulate functions as crucial as DNA replication and gene expression in response to environmental messages and then it was duplicated at the plasma membrane in order to allow cross-talking between extracellular signals and the genome in multicellular organisms. This pioneering

Acknowledgments

This work was supported by: Associazione Italiana Ricerca sul Cancro (AIRC Regional Grants); Italian MIUR FIRB 2001 and COFIN 2005; Carisbo Foundation.

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