mTOR signaling in lymphangioleiomyomatosis

Abstract

The protein mammalian target of rapamycin (mTOR) plays a central role in cell growth and proliferation. Excessive mTOR activity is a prominent feature of many neoplasms and hamartoma syndromes, including lymphangioleiomyomatosis (LAM), a destructive lung disease that causes progressive respiratory failure in women. Although pharmacological inhibitors of mTOR should directly target the pathogenesis of these disorders, their clinical efficacy has been suboptimal. Recent scientific findings reviewed here have greatly improved our understanding of mTOR signaling mechanisms, provided new insights into the control of cell growth and proliferation, and facilitated the development of new therapeutic approaches in LAM, as well as other neoplastic disorders that exhibit excessive mTOR activity.

FIG. 1.

Structural domains and motifs in mTOR. mTOR consists of 2549 amino acids organized in several structural domains. The N-terminal portion of mTOR contains multiple HEAT (Huntington, Elongation factor 3, A subunit of type 2A protein phosphatase (PP2A), and TOR). The FAT (FRAP, Ataxia telangiectasia mutated (ATM), Transformation/transcription domain associated protein (TRRAP)) and FAT c-terminal (FATc) domains flank the kinase domain, are required for kinase activity, and appear to cooperatively bind certain mTOR-interacting proteins. Highly conserved, and homologous to that in ATM and ATR, the c-terminal kinase domain (PI3_PI4_kinase) contains the serine/threonine kinase active site. The FKBP12-rapamycin-binding (FRB) domain binds the rapamycin/FKBP12 complex or phosphatidic acid.^,

FIG. 2.

Composition of the mTOR core complexes. mTOR complexes integrate mitogenic and metabolic signals, and control anabolic or catabolic cellular functions as appropriate. mTORC1, as defined by the presence of raptor, is shown to the left of mTORC2, which is defined by its association with rictor. Other adapter proteins that coordinate the functions of mTOR complexes are also shown.

FIG. 3.

Coordination of mTORC1 and mTORC2 signaling activities. mTOR signaling can be organized into concentric spheres consisting from center to periphery of the mTORCs (center), their regulatory interaction partners, proteins that indirectly modify mTORC activity or mediate mTORC functions, and the mTORC-related physiological stimuli or functions. Proteins that modify mTORC activity are above the horizontal line, whereas those which mediate mTOR functions are below. Although multiple feedback and crosstalk mechanisms occur, the directionality of mTOR signaling is depicted in the center, with the mTOR complexes acting as signal integrators. Color images available online at www.liebertonline.com/lrb.