Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an
adapter protein that is encoded in humans by the RPTORgene.[5][6][7] Two
mRNAs from the gene have been identified that encode proteins of 1335 (isoform 1) and 1177 (isoform 2)
amino acids long.
Gene and expression
The human gene is located on human chromosome 17 with location of the cytogenic band at 17q25.3.[7]
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.[8] In the cell, RPTOR is present in
cytoplasm,
lysosomes, and cytoplasmic granules. Amino acid availability determines RPTOR targeting to lysosomes. In stressed cells, RPTOR associates with
SPAG5 and accumulates in
stress granules, which significantly reduces its presence in
lysosomes.[9][10]
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
mTOR pathway. The adapter protein and
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
mTOR kinase. RPTOR also has a positive role in maintaining cell size and
mTOR protein expression. The association of
mTOR and RPTOR is stabilized by nutrient deprivation and other conditions which suppress the
mTOR pathway.[8] Multiple transcript variants exist for this gene which encode different isoforms.[7]
Structure
RPTOR is a 150 kDa
mTOR binding protein that is part of the mammalian target of rapamycin complex 1 (
mTORC1). This complex contains
mTOR,
MLST8, RPTOR,
AKT1S1/PRAS40, and
DEPTOR.
mTORC1 both binds to and is inhibited by FKBP12-rapamycin.
mTORC1 activity is upregulated by
mTOR and
MPAK8 by insulin-stimulated phosphorylation at Ser-863.[11][12]MAPK8 also causes phosphorylation at Ser-696, Thr-706, and Ser-863 as a result of osmotic stress.[13]AMPK causes phosphorylation in the event of nutrient starvation and promotes
14-3-3 binding to raptor, which downregulates the
mTORC1 complex.[14]RPS6KA1 stimulates
mTORC1 activity by phosphorylating at Ser-719, Ser-721, and Ser-722 as a response to growth factors.
Interactions
mTORC1 binds to and is inhibited by FKBP12-rapamycin
RPTOR binds to 4EBP1 and
RPS6KB1 directly whether or not it is associated with
mTOR[15]
RPTOR binds to poorly phosphorylated or non-phosphorylated
EIF4EBP1 preferentially, which is important for
mTOR to be able to catalyze phosphorylation.[6][15][16][17][18][19][20][21]
RPTOR interacts with
ULK1. This interaction depends on nutrients and is reduced in the case of starvation.[22]
When RPTOR is phosphorylated by
AMPK, it interacts with
14-3-3 protein and inhibits its activity.[14]
RPTOR interacts with
SPAG5, which competes with
mTOR for binding RPTOR and causes decreased
mTORC1 formation.
RPTOR interacts with
G3BP1. Oxidative stress increases the formation of the complex formed with RPTOR,
G3BP1, and
SPAG5[10]
The clinical significance of RPTOR is primarily due to its involvement in the
mTOR pathway, which plays roles in
mRNA translation,
autophagy, and cell growth. Mutations in the
PTEN tumor suppressor gene are the best known genetic deficiencies in cancer which affect
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)P2 to create PtdIns(3,4,5)P3 (
PIP3).
PIP3 is a membrane-docking site for
AKT and
PDK1. In turn, active
PDK1, along with
mTORC1, phosphorylates S6K in the part of the
mTOR pathway which promotes protein synthesis and cell growth.[39]
The
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
mTORC1.[40][41] mTORC1 phosphorylates Atg13 and stops it from forming the ULK1 kinase complex. This inhibits autophagy, the major degradation pathway in eukaryotic cells.[42] Because
mTORC1 inhibits
autophagy and stimulates cell growth, it can cause damaged proteins and cell structures to accumulate. For this reason, dysfunction in the process of
autophagy can contribute to several diseases, including cancer.[43]
The
mTOR pathway is important in many cancers. In cancer cells, astrin is required to suppress
apoptosis during stress. Astrin recruits RPTOR to
stress granules, inhibiting
mTORC1 association and preventing
apoptosis induced by
mTORC1 hyperactivation. Because astrin is frequently upregulated in tumors, it is a potential target to sensitize tumors to
apoptosis through the
mTORC1 pathway.[10]
RPTOR is overexpressed in
pituitary adenoma, and its expression increases with tumor staging. RPTOR could be valuable in the prediction and prognosis of
pituitary adenoma due to this correlation between protein expression and the growth and invasion of the tumor.[44]
As a drug target
mTOR is found in two different complexes. When it associates with
rapamycin-insensitive companion of mTOR (rictor), the complex is known as
mTORC2 and it is insensitive to
rapamycin. However, the complex
mTORC1 formed by association with accessory protein RPTOR is sensitive to
rapamycin.
Rapamycin is a
macrolide which is an immunosuppressant in humans that inhibits
mTOR by binding to its intracellular receptor
FKBP12. In many cancers, hyperactive
AKT signaling leads to increased
mTOR signaling, so
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.[39]
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