RPTOR

Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter is_associated_with::protein that is encoded in humans by the RPTOR is_associated_with::gene. Two mRNAs from the gene have been identified that encode proteins of 1335 (isoform 1) and 1177 (isoform 2) is_associated_with::amino acids long.

Gene and expression
The human gene is located on human chromosome 17 with location of the cytogenic band at 17q25.3.

Location
RPTOR is highly expressed in skeletal muscle and is somewhat less present in brain, lung, small intestine, kidney, and placenta tissue. Isoform 3 is widely expressed and most highly expressed in the nasal mucosa and pituitary. The lowest levels occur in the spleen. In the cell, RPTOR is present in is_associated_with::cytoplasm, is_associated_with::lysosomes, and cytoplasmic granules. Amino acid availability determines RPTOR targeting to lysosomes. In stressed cells, RPTOR associates with is_associated_with::SPAG5 and accumulates in is_associated_with::stress granules, which significantly reduces its presence in is_associated_with::lysosomes...

Function
RPTOR encodes part of a signaling pathway regulating cell growth which responds to nutrient and insulin levels. RPTOR is an evolutionarily conserved protein with multiple roles in the is_associated_with::mTOR pathway. The adapter protein and is_associated_with::mTOR kinase form a stoichiometric complex. The encoded protein also associates with eukaryotic initiation factor 4E-binding protein-1 and ribosomal protein S6 kinase. It upregulates S6 kinase, the downstream effector ribosomal protein, and it downregulates the is_associated_with::mTOR kinase. RPTOR also has a positive role in maintaining cell size and is_associated_with::mTOR protein expression. The association of is_associated_with::mTOR and RPTOR is stabilized by nutrient deprivation and other conditions which suppress the is_associated_with::mTOR pathway. Multiple transcript variants exist for this gene which encode different isoforms.

Structure
RPTOR is a 150 kDa is_associated_with::mTOR binding protein that is part of the mammalian target of rapamycin complex 1 (is_associated_with::mTORC1). This complex contains is_associated_with::mTOR, is_associated_with::MLST8, RPTOR, is_associated_with::AKT1S1/PRAS40, and is_associated_with::DEPTOR. is_associated_with::mTORC1 both binds to and is inhibited by FKBP12-rapamycin. is_associated_with::mTORC1 activity is upregulated by is_associated_with::mTOR and is_associated_with::MPAK8 by insulin-stimulated phosphorylation at Ser-863. is_associated_with::MAPK8 also causes phosphorylation at Ser-696, Thr-706, and Ser-863 as a result of osmotic stress. is_associated_with::AMPK causes phosphorylation in the event of nutrient starvation and promotes is_associated_with::14-3-3 binding to raptor, which downregulates the is_associated_with::mTORC1 complex. is_associated_with::RPS6KA1 stimulates is_associated_with::mTORC1 activity by phosphorylating at Ser-719, Ser-721, and Ser-722 as a response to growth factors.

Interactions

 * is_associated_with::mTORC1 binds to and is inhibited by FKBP12-rapamycin
 * RPTOR binds to 4EBP1 and is_associated_with::RPS6KB1 directly whether or not it is associated with is_associated_with::mTOR
 * RPTOR binds to poorly phosphorylated or non-phosphorylated is_associated_with::EIF4EBP1 preferentially, which is important for is_associated_with::mTOR to be able to catalyze phosphorylation.
 * RPTOR interacts with is_associated_with::ULK1. This interaction depends on nutrients and is reduced in the case of starvation.
 * When RPTOR is phosphorylated by AMPK, it interacts with is_associated_with::14-3-3 protein and inhibits its activity.
 * RPTOR interacts with is_associated_with::SPAG5, which competes with is_associated_with::mTOR for binding RPTOR and causes decreased is_associated_with::mTORC1 formation.
 * RPTOR interacts with is_associated_with::G3BP1. Oxidative stress increases the formation of the complex formed with RPTOR, is_associated_with::G3BP1, and is_associated_with::SPAG5

RPTOR has also been shown to interact with:
 * is_associated_with::FKBP1A,
 * is_associated_with::P70-S6 Kinase 1
 * is_associated_with::RHEB,
 * is_associated_with::RICTOR, and
 * is_associated_with::mammalian target of rapamycin (mTOR),

Signaling in cancer
The clinical significance of RPTOR is primarily due to its involvement in the is_associated_with::mTOR pathway, which plays roles in is_associated_with::mRNA translation, is_associated_with::autophagy, and cell growth. Mutations in the PTEN tumor suppressor gene are the best known genetic deficiencies in cancer which affect is_associated_with::mTOR signaling. These mutations are frequently found in a very large variety of cancers, including prostate, breast, lung, bladder, melanoma, endometrial, thyroid, brain, and renal carcinomas. PTEN inhibits the lipid-kinase activity of class I PtdIns3Ks, which phosphorylate PtdIns(4,5)P$2$ to create PtdIns(3,4,5)P$3$ (is_associated_with::PIP3). is_associated_with::PIP3 is a membrane-docking site for is_associated_with::AKT and is_associated_with::PDK1. In turn, active is_associated_with::PDK1, along with is_associated_with::mTORC1, phosphorylates S6K in the part of the is_associated_with::mTOR pathway which promotes protein synthesis and cell growth.

The is_associated_with::mTOR pathway has also been found to be involved in aging. Studies with C. elegans, fruitflies, and mice have shown that the lifespan of the organism is significantly increased by inhibiting is_associated_with::mTORC1. mTORC1 phosphorylates Atg13 and stops it from forming the ULK1 kinase complex. This inhibits autophagy, the major degradation pathway in eukaryotic cells. Because is_associated_with::mTORC1 inhibits is_associated_with::autophagy and stimulates cell growth, it can cause damaged proteins and cell structures to accumulate. For this reason, dysfunction in the process of is_associated_with::autophagy can contribute to several diseases, including cancer.

The is_associated_with::mTOR pathway is important in many cancers. In cancer cells, astrin is required to suppress is_associated_with::apoptosis during stress. Astrin recruits RPTOR to is_associated_with::stress granules, inhibiting is_associated_with::mTORC1 association and preventing is_associated_with::apoptosis induced by is_associated_with::mTORC1 hyperactivation. Because astrin is frequently upregulated in tumors, it is a potential target to sensitize tumors to is_associated_with::apoptosis through the is_associated_with::mTORC1 pathway.

RPTOR is overexpressed in is_associated_with::pituitary adenoma, and its expression increases with tumor staging. RPTOR could be valuable in the prediction and prognosis of is_associated_with::pituitary adenoma due to this correlation between protein expression and the growth and invasion of the tumor.

As a drug target
is_associated_with::mTOR is found in two different complexes. When it associates with rapamycin-insensitive companion of mTOR (rictor), the complex is known as is_associated_with::mTORC2 and it is insensitive to is_associated_with::rapamycin. However, the complex is_associated_with::mTORC1 formed by association with accessory protein RPTOR is sensitive to is_associated_with::rapamycin. is_associated_with::Rapamycin is a is_associated_with::macrolide which is an immunosuppressant in humans that inhibits is_associated_with::mTOR by binding to its intracellular receptor is_associated_with::FKBP12. In many cancers, hyperactive is_associated_with::AKT signaling leads to increased is_associated_with::mTOR signaling, so is_associated_with::rapamycin has been considered as an anti-cancer therapeutic for cancers with PTEN inactivation. Numerous clinical trials involving rapamycin analogs, such as CCI-779, RAD001, and AP23573, are ongoing. Early reports have been promising for renal-cell carcinoma, breast carcinomas, and non-small-cell lung carcinomas.