hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling
Introduction
It has been known for nearly a decade that the mammalian target of rapamycin (mTOR) Complex1 is exquisitely sensitive to nutrients. However, there has been little understanding of the underlying mechanisms which mediate this response, despite an increasing awareness of the importance of this pathway in metabolic syndromes such as diabetes, obesity and cancer. Here we review the recent finding that hVps34 mediates nutrient signaling to mTOR. We also discuss a potential framework to rationalize the distinct roles played by hVps34 in the control of growth versus autophagy.
Section snippets
mTOR Complex1/S6K1
mTOR and its downstream effector S6 kinase 1 (S6K1), as well as initiation factor 4E binding protein (4E-BP1), have emerged as critical signaling components in the development, differentiation and growth of the organism [1], as well as in the maintenance of normal metabolic homeostasis [2, 3]. In the case of S6K1, mTOR appears to influence these processes largely at the level of protein synthesis, through S6K1 phosphorylation of target proteins, such as ribosomal protein S6 [4], elongation
hVps34 and mTOR
The link between hVps34 and mTOR Complex1 signaling emerged independently in studies designed to elucidate the mechanism by which nutrient input, particularly of amino acids and glucose, leads to increased S6K1 T389 phosphorylation as a readout of mTOR Complex1 activation [34•, 35••]. Initially it was presumed that amino acids affected mTOR Complex1/S6K1 by acting through the generic class 1 PI3K branch of this pathway [35••]. In the absence of TSC1/TSC2, although mTOR Complex1/S6K1 activation
Autophagy and endosome signaling
hVps34 is known to play a critical role in autophagy, and has been shown to directly interact with the autophagic gene beclin. Beclin was first identified as a Bcl-2-interacting protein in a yeast two-hybrid screen [61]. Subsequently it has been shown to be a haploinsufficient tumor suppressor gene [62, 63], and it has been demonstrated that overexpression of Bcl-2 disrupts the hVps34–beclin interaction [64•]. Moreover, it is hypothesized that, in a nutrient-replete setting, Bcl-2 inhibits
Future perspectives
Given the ability of mTOR Complex1 to suppress autophagy, and the importance of both endosome trafficking and autophagy to the malignant phenotype, it will be critical to identify the mechanisms by which these two pathways interact at the intracellular level. Currently, hVps34 and hVps15 are the only known components of the pathway linking nutrient input to mTOR Complex1 activation. Thus, identifying the upstream and downstream elements of this pathway will be critical to deciphering the
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgments
We thank M Daston for editing and members of Kozma/Thomas laboratory for discussions and insights concerning this review. GT is supported by a U01 grant of the Mouse Models of Human Cancer Consortium (CA-84292-06) and an R01 grant (DK-73802-01) from the NIH. SK is supported by a R01 grant (CA-120475-01) from the NIH.
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