PI3K Signaling in Tissue Hyper-Proliferation: From Overgrowth Syndromes to Kidney Cysts.

Miriam Martini,Giovanni Ferrero,Maria De Santis,Valentina Sala,Emilio Hirsch

doi:10.3390/cancers9040030

Miriam Martini, Giovanni Ferrero + Show 3 more

Open Access

https://doi.org/10.3390/cancers9040030

Copy DOI

Journal: Cancers	Publication Date: Mar 29, 2017
Citations: 32	License type: CC BY 4.0

Affiliation: University of Turin

Abstract

The members of the PhosphoInositide-3 Kinase (PI3K) protein family are well-known regulators of proliferative signals. By the generation of lipid second messengers, they mediate the activation of AKT/PKB (AKT) and mammalian Target Of Rapamycin (mTOR) pathways. Although mutations in the PI3K/AKT/mTOR pathway are highly characterized in cancer, recent evidence indicates that alterations in the proliferative signals are major drivers of other diseases such as overgrowth disorders and polycystic kidney disease. In this review, we briefly summarize the role of the PI3K/AKT/mTOR pathway in cell proliferation by comparing the effect of alterations in PI3K enzymes in different tissues. In particular, we discuss the most recent findings on how the same pathway may lead to different biological effects, due to the convergence and cooperation of different signaling cascades.

Highlights

Tissue proliferation is a tightly regulated process in the organism, from embryonic development to adult life
We report the recent findings in PhosphoInositide-3 Kinase (PI3K)/AKT/mammalian Target Of Rapamycin (mTOR) pathway alterations, in the well-known context of cancer, and in other proliferative disorders such as overgrowth syndrome and polycystic kidney disease
These two transmembrane proteins are encoded by PKD1 or PKD2 genes, which are mutated in autosomal-dominant polycystic kidney disease (ADPKD), a genetic disorder characterized by uncontrolled proliferation of renal cells with the consequent formation of cysts and loss of renal function [58,59]

Summary

Introduction

Tissue proliferation is a tightly regulated process in the organism, from embryonic development to adult life. One of the main regulators of cell proliferation is the PhosphoInositide-3 Kinase (PI3K)/AKT/PKB (AKT)/mammalian Target Of Rapamycin (mTOR). This second messenger acts as a docking site for proteins that contain a pleckstrin homology (PH) domain, such as AKT, which is one of the major downstream effectors of PI3K and activates a series of downstream signaling pathways, including the AKT/mammalian target of rapamycin pathway (mTOR). The primary cilium plays a key role in the signaling pathways of several proteins, such as Polycystins 1 and 2 (PC1/2) [5], which are involved in the control of the fluid flow and tubular cell proliferation. PI3K-C2α modulates the trafficking of cargo proteins such as PC2 along the primary cilium, allowing polycystin-mediated control of proliferative signals in kidney tubular cells [7]. We report the recent findings in PI3K/AKT/mTOR pathway alterations, in the well-known context of cancer, and in other proliferative disorders such as overgrowth syndrome and polycystic kidney disease

PI3K Somatic Mutations Leading to Cancer and Proliferative Disorders

The PIK3CA-Related Spectrum of Overgrowth Syndromes

PI3Ks Inhibitors as a Therapeutic Challenge in Overgrowth Syndromes

Findings

Conclusions