The Role of PTEN in β-Cell Growth.

This paper describes the biological functions of PTEN and the PTEN regulated signaling pathway in pancreatic  -cells. PTEN has been shown to regulate the regeneration of  -cells. We review the pathways that are controlled by PTEN signaling and their functions in  -cell regeneration. In particular, we describe the unique effect of Pten deletion in  -cells. Unlike its effect in other tissues, Pten deletion does not lead to tumor formation but does enhance  -cell proliferation and function. In addition to the literature review, we also report new results exploring PTEN loss in adult  - cells. We demonstrate that inducing PTEN loss in adult cells has the same regenerative effects previously found for prenatal deletion. PTEN (phosphatase and tensin homologue deleted on chromosome 10) (also named MMAC1/TEP1) was discovered in 1997 independently by three laboratories as a tumor suppressor of which the expression is often lost in tumors (1-3). Later studies established that PTEN is a negative regulator of a major cell growth and survival signaling pathway, namely the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway (4, 5). In this paper, we describe the canonical signaling regulated by PTEN as well as a variant of PTEN signaling that is localized in the cell nucleus. We also summarized the ways that PTEN can be regulated transcriptionally, post-transcriptionally and through regulation of its subcellular localization. We review the biological functions of PTEN and its downstream target proteins. The role that proteins downstream of PTEN play in  -cells had recently been reviewed (6). Here, we focus on the specific effects of PTEN on  -cell regeneration and islet tumor development and issues relating to these effects. Toward this end, we review the phenotypes of several AKT transgenic and Pten deletion studies and report new observations that we have made with Pten mutant mice. Lastly, we report new results that illustrate the specific effects of Pten deletion in  -cells and discuss the unique biology of  -cells that requires further research. PTEN REGULATED SIGNALING PATHWAYS Canonical Signaling Pathways Regulated by PTEN PTEN is a dual lipid and protein phosphatase. The protein structure of PTEN shares homology with known protein phosphatases and is capable of dephosphorylating phospho-peptides as well as phospho-lipids in vitro. The biological effects of PTEN, however are dominated by its ability to dephosphorylate the lipid substrate phosphati- dylinositol-3,4,5-triphosphate (PI-3,4,5-P3) whereas protein