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FRAP1

MIM.601231 1p36.2

Friday 23 April 2004

WKP

Definition: mTOR (FRAP1) is a serine-threonine kinase (STKs ). It links environmental conditions to translation initiation in eukaryotic cells.

Growth factors activate TOR signaling through the PI3K/Akt pathway, whereas nutritional signals and energy charge regulate mTOR via the AMPK/TSC/Rheb pathway.

An important function of mTor is to regulate the protein synthesis via phosphorylating its substrates p70S6K1 and 4EBP1.

The target of rapamycin (TOR) is an evolutionarily conserved kinase that integrates signals from nutrients (amino acids and energy) and growth factors (in higher eukaryotes) to regulate cell growth and cell cycle progression coordinately.

Reflecting its critical role in integrating cell growth and division with the cellular nutritional environment, the mammalian target of rapamycin *(mTOR) is a highly conserved downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway.

mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1.

As a consequence of inhibiting its downstream messengers, mTOR inhibitors prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein (RB) phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause GI phase arrest.

In mammals, TOR is best known to regulate translation through the ribosomal protein S6 kinases (S6Ks) and the eukaryotic translation initiation factor 4E-binding proteins.

Consistent with the contribution of translation to growth, TOR regulates cell, organ, and organismal size.

TSC1 and TSC2

The identification of the tumor suppressor proteins tuberous sclerosis-1 and tuberous sclerosis-2 (TSC1 and TSC2) and Ras-homolog enriched in brain (Rheb) has biochemically linked the TOR and phosphatidylinositol 3-kinase (PI3K) pathways, providing a mechanism for the crosstalk that occurs between these pathways.

PTEN

PTEN suppresses phosphoinositol-3-kinase (PI3K) signaling, thereby down-regulating downstream mediators, including the oncogenic serine-threonine kinase AKT1, which in turn regulates the mTOR (mammalian target of rapamycin) growth pathway.

mTOR organization

The N-terminus of mTOR contains two tandem arrays of HEAT (Huntington, Elongation factor 3A, A subunit of PP2A, and TOR1) repeat domains, which likely mediate protein–protein interactions.

Immediately downstream of the HEAT repeat region lies the FAT (FRAP, ATM, and TRRAP) domain, which is relatively conserved in these three PIKK family members. The FAT domain is followed by the PtdIns 3-kinase related catalytic domain, and in turn by a second region of homology termed FAT-C. The FAT and FAT-C might contribute to the active conformation of the intervening kinase domain.

A unique feature of mTOR is the FRB (FKBP12•rapamycin-binding) domain, a conserved stretch of 110 amino acids, found in all eukaryotic TOR orthologs. The FRB domain forms a deep hydrophobic cleft that serves as the high-affinity binding site for the inhibitory FKBP12•rapamycin complex.

mTORCs signaling complexes

In mammalian cells, mTOR forms part of two structurally and functionally distinct protein complexes, termed mTORC1 and mTORC2.

MTORC1

The mTORC1 complex is directly inhibited by FKBP12•rapamycin (and the rapalogs, Torisel, RAD001, and AP23573), as well as the small molecule dual PI3K-mTOR inhibitors, LY294002 and PtdIns-103, and is uniquely defined by the presence of the mTOR-interacting protein, Raptor. This complex also contains a third subunit, termed mLST8, which is shared with mTORC2.

In all eukaryotic cell types, TORC1 carries out many of the primordial regulatory functions of TOR, particularly nutrient sensing, and the orchestration of cell growth and stress responses. The two best-characterized mTORC1 substrates, elongation factor 4E binding protein 1 (4E-BP1) and ribosomal protein S6 kinase-1 (S6K1), are components of the translational control machinery and mediate cap-dependent translation and ribosome biogenesis, respectively.

In addition, mTORC1 negatively regulates autophagy and cellular adaptation to hypoxia).

mTORC2

The mTORC2 complex is not inhibited by rapamycin or its analogs, but is inhibited by LY294002 and PtdIns-103. In addition to the shared LST8 subunit, mTORC2 contains three unique proteins: Rictor, mSIN1, and the recently described Protor-1 (also called PRR5).

Although Rictor is considered the defining subunit of mTORC2, the expression of several isoforms of hSin1 can further subdivide mTORC2 into functionally different sub-complexes.

AKT activity and signaling is stimulated by mTORC2 by phosphorylation at Ser473. Furthermore, mTORC also regulates PKC-α phosphorylation and cytoskeletal organization.

Pathology

Constitutive activation of the PI3K/Akt kinases occur in human leukemias. FLT3, VEGF, and BCR-ABL mediate their activities via mTOR.

Therapeutics

mTOR is emerging as a novel antitumor target, since the TOR inhibitor rapamycin appears to be effective against tumors resulting from aberrantly high PI3K signaling. Not only may inhibition of TOR be effective in cancer treatment, but rapamycin is an FDA-approved immunosuppressive and cardiology drug.

Clinical trials are currently underway to evaluate mTOR inhibition as a viable cancer treatment for PTEN-null cancers. The anti-tumor response to mTOR inhibition occurs through independent apoptotic and Hif-1α regulatory pathways.

New rapamycin analogs including CCI-779, RAD001, and AP23573, are entering clinical studies for patients with hematologic malignancies.