Investigating the duality of Inpp4b function in the cellular transformation of mouse fibroblasts.

Emily Marie Mangialardi,Brittany Salmon,Leonardo Salmena,Jean Vacher,Keyue Chen

doi:10.18632/oncotarget.27293

Abstract

Inositol Polyphosphate 4-Phosphatase, Type II (INPP4B) is a tumour suppressor in breast, ovarian, prostate, thyroid and other cancers, attributed to its ability to reduce oncogenic Akt-signaling. However, emerging studies show that INPP4B also has tumour-promoting properties in cancers including acute myeloid leukemia, colon cancer, melanoma and breast cancer. Together these findings suggest that INPP4B may be a context dependent cancer gene. Whether INPP4B functions solely in a tumour suppressing or tumour promoting manner, or both in non-transformed cells is currently not clear. In this study, consequences of deficiency and overexpression of INPP4B on cellular transformation was investigated using a mouse embryonic fibroblast (MEF) model of cellular transformation. We observed that neither deficiency nor overexpression of INPP4B was sufficient to induce neoplastic transformation, alone or in combination with H-RasV12 or E1A overexpression. However, Inpp4b-deficiency did cooperate with SV40 T-Large-mediated cellular transformation, a finding which was associated with increased phosphorylated-Akt levels. Transformation and phosphorylated-Akt levels were dampened upon overexpression of INPP4B in SV40 T-Large-MEF. Together, our findings support a model where INPP4B function suppresses transformation mediated by SV40 T-Large, but is inconsequential for Ras and E1A mediated transformation.

Highlights

The phosphoinositide-3-kinase (PI3K) signaling pathway regulates cell survival, proliferation, metabolism and various other processes linked to cell growth
Growth characteristics of primary mouse embryonic fibroblast (MEF) was evaluated in short term growth assays where we observed no significant differences in the mean growth rates of Inpp4b+/+, Inpp4b+/- and Inpp4b-/- MEF (Figure 1C)
To investigate the necessity for Inpp4b in cellular transformation, we examined the consequences of Inpp4b deficiency on H-RasV12/Adenovirus early region 1A (E1A) mediated MEF transformation

Summary

Introduction

The phosphoinositide-3-kinase (PI3K) signaling pathway regulates cell survival, proliferation, metabolism and various other processes linked to cell growth. The PI3K pathway is activated by growth-factor mediated activation of receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) which transduce signals through class I PI3K via phosphorylation of the 3-hydroxyl group of the inositol ring of phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] to generate phosphatidylinositol-3,4,5-. PIP3 is subsequently dephosphorylated by either PTEN to form phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] or by SHIP phosphatases to form phosphatidylinositol-. The 3’phosphorylated phosphatidylinositols like PIP3 and PtdIns(3,4)P2 recruit cytosolic proteins containing pleckstrin homology (PH). Domains, such as the serine/threonine kinase Akt. Once recruited to membranes, the kinase activity of Akt is activated by phosphorylation to promote downstream signaling to cell survival, growth, proliferation, cell migration and angiogenesis, through phosphorylation of specific intracellular protein substrates [3]

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