The PI3K/Akt/mTOR pathway in polycystic kidney disease: A complex interaction with polycystins and primary cilium

• Published in: Cellular signalling 2020-02, Vol.66, p.109468-109468, Article 109468
• Main Authors: Margaria, Jean Piero, Campa, Carlo Cosimo, De Santis, Maria Chiara, Hirsch, Emilio, Franco, Irene
• Format: Article
• Language: English
• Subjects: Cancer; Cell Proliferation; Cilia - pathology; Humans; Kidney Tubules - metabolism; Kidney Tubules - pathology; mTOR; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositides; PI3K; PIK3C2A; Polycystic kidney disease; Polycystic Kidney Diseases - metabolism; Polycystins; Primary cilium; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; TRPP Cation Channels - metabolism
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2019.109468

Over-activation of the PI3K/Akt/mTOR network is a well-known pathogenic event that leads to hyper-proliferation. Pharmacological targeting of this pathway has been developed for the treatment of multiple diseases, including cancer. In polycystic kidney disease (PKD), the mTOR cascade promotes cyst growth by boosting proliferation, size and metabolism of kidney tubule epithelial cells. Therefore, mTOR inhibition has been tested in pre-clinical and clinical studies, but only the former showed positive results. This review reports recent discoveries describing the activity and molecular mechanisms of mTOR activation in tubule epithelial cells and cyst formation and discusses the evidence of an upstream regulation of mTOR by the PI3K/Akt axis. In particular, the complex interconnections of the PI3K/Akt/mTOR network with the principal signaling routes involved in the suppression of cyst formation are dissected. These interactions include the antagonism and the reciprocal negative regulation between mTOR complex 1 and the proteins whose deletion causes Autosomal Dominant PKD, the polycystins. In addition, the emerging role of phopshoinositides, membrane components modulated by PI3K, will be presented in the context of primary cilium signaling, cell polarization and protection from cyst formation. Overall, studies demonstrate that the activity of various members of the PI3K/Akt/mTOR network goes beyond the classical transduction of mitogenic signals and can impact several aspects of kidney tubule homeostasis and morphogenesis. These properties might be useful to guide the establishment of more effective treatment protocols to be tested in clinical trials. •Over-activation of the PI3K/Akt/mTOR pathway leads to hyper-proliferation in both cancer and kidney cysts•Successful outcome of mTOR inhibition in pre-clinical studies is not reproduced in clinical trials for PKD•Reciprocal regulation of mTOR-complex 1 and polycystin-1 affects kidney tubule homeostasis and PKD progression•Emerging role of PI3K-pathway members PIK3C2A and INPP5E in primary cilium-signalling and protection from cyst formation