PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control

Abstract

The PI3K-Akt pathway is a major survival pathway activated in cancer. Efforts to develop targeted therapies have not been fully successful, mainly because of extensive internal intrapathway or external interpathway negative feedback loops or because of networking between pathway suppressors. The PTEN tumor suppressor is the major brake of the pathway and a common target for inactivation in somatic cancers. This review will highlight the networking of PTEN with other inhibitors of the pathway, relevant to cancer progression. PTEN constitutes the main node of the inhibitory network, and a series of convergences at different levels in the PI3K-Akt pathway, starting from those with growth factor receptors, will be described. As PTEN exerts enzymatic activity as a phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) phosphatase, thus opposing the activity of PI3K, the concerted actions to increase the availability of PIP(3) in cancer cells, relying either on other phosphoinositide enzymes or on the intrinsic regulation of PTEN activity by other molecules, will be discussed. In particular, the synergy between PTEN and the circle of its direct interacting proteins will be brought forth in an attempt to understand both the activation of the PI3K-Akt pathway and the connections with other parallel oncogenic pathways. The understanding of the interplay between the modulators of the PI3K-Akt pathway in cancer should eventually lead to the design of therapeutic approaches with increased efficacy in the clinic.

Keywords: Akt; PI3K; PTEN; protein interactions; synergy.

Figure 1.

Nonlinear signaling through the PI3K-Akt pathway. Growth factors activate receptor tyrosine kinases (RTKs) that further activate parallel growth pathways. The MAPK pathway, which signals via Ras and downstream effectors, is an example of a linear growth-promoting pathway. The PI3K-Akt pathway is an example of a nonlinear pathway that signals through protein and lipid effectors and through layers of oncoproteins (red) and growth suppressors (blue). Negative feedback loops of the PI3K-Akt pathway are shown in green (repressing) or orange (activating). The effectors of the pathway whose alterations show combinatorial additive effects with PTEN inactivation in cancers are encircled.

Figure 2.

Diagram of PTEN domain structure.

Figure 3.

Three categories of PTEN-interacting proteins. Examples in each category are shown in red (oncoproteins) or blue (tumor suppressor proteins) and discussed in the text. PTEN phosphatase-dependent (P-d) or phosphatase-independent (P-i) connections resulting in oncogenic and tumor suppressor effects relevant for human cancers are shown with red and blue arrows, respectively.