Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the ''RPTOR''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Two mRNAs from the gene have been identified that encode proteins of 1335 (isoform 1) and 1177 (isoform 2)

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

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

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

lysosomes A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

, 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

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. Multiple transcript variants exist for this gene which encode different isoforms.

Structure

RPTOR is a 150 kDa mTOR binding protein that is part of the mammalian target of rapamycin complex 1 (

mTORC1 mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis. mTOR Complex 1 (mTORC1) is comp ...

). This complex contains mTOR, MLST8, RPTOR, AKT1S1/PRAS40, and DEPTOR.

both binds to and is inhibited by FKBP12-rapamycin.

activity is upregulated by mTOR and MPAK8 by insulin-stimulated phosphorylation at Ser-863. MAPK8 also causes phosphorylation at Ser-696, Thr-706, and Ser-863 as a result of osmotic stress. AMPK causes phosphorylation in the event of nutrient starvation and promotes

14-3-3 14-3-3 proteins are a family of conserved regulatory molecules that are expressed in all eukaryotic cells. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and tran ...

binding to raptor, which downregulates the

complex. RPS6KA1 stimulates

activity by phosphorylating at Ser-719, Ser-721, and Ser-722 as a response to growth factors.

Interactions

binds to and is inhibited by FKBP12-rapamycin * RPTOR binds to 4EBP1 and RPS6KB1 directly whether or not it is associated with mTOR * RPTOR binds to poorly phosphorylated or non-phosphorylated EIF4EBP1 preferentially, which is important for mTOR to be able to catalyze phosphorylation. * RPTOR interacts with ULK1. This interaction depends on nutrients and is reduced in the case of starvation. * When RPTOR is phosphorylated by AMPK, it interacts with

14-3-3 protein 14-3-3 proteins are a family of conserved regulatory molecules that are expressed in all eukaryotic cells. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and tra ...

and inhibits its activity. * RPTOR interacts with SPAG5, which competes with mTOR for binding RPTOR and causes decreased

formation. * RPTOR interacts with G3BP1. Oxidative stress increases the formation of the complex formed with RPTOR, G3BP1, and SPAG5 RPTOR has also been shown to interact with: * FKBP1A, *

P70-S6 Kinase 1 Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase (p70S6K, p70-S6K), is an enzyme (specifically, a protein kinase) that in humans is encoded by the ''RPS6KB1'' gene. It is a serine/threonine kinase that acts downstream of Phos ...

* RHEB, * RICTOR, and *

mammalian target of rapamycin The mammalian target of sirolimus, rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''M ...

(mTOR),

Clinical significance

Signaling in cancer

The clinical significance of RPTOR is primarily due to its involvement in the mTOR pathway, which plays roles in mRNA translation,

autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...

, 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)P to create PtdIns(3,4,5)P ( PIP3). PIP3 is a membrane-docking site for AKT and PDK1. In turn, active PDK1, along with

, phosphorylates S6K in the part of the mTOR pathway which promotes protein synthesis and cell growth. 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 phosphorylates Atg13 and stops it from forming the ULK1 kinase complex. This inhibits autophagy, the major degradation pathway in eukaryotic cells. Because

inhibits

and stimulates cell growth, it can cause damaged proteins and cell structures to accumulate. For this reason, dysfunction in the process of

can contribute to several diseases, including cancer. The mTOR pathway is important in many cancers. In cancer cells, astrin is required to suppress

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

during stress. Astrin recruits RPTOR to stress granules, inhibiting

association and preventing

induced by

hyperactivation. Because astrin is frequently upregulated in tumors, it is a potential target to sensitize tumors to

through the

pathway. RPTOR is overexpressed in

pituitary adenoma Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas.pituitary adenoma Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas.

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 Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ rejection, organ transplant rejection, treat a rare lung disease called lymphang ...

. However, the complex

formed by association with accessory protein RPTOR is sensitive to

Rapamycin Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ rejection, organ transplant rejection, treat a rare lung disease called lymphang ...

is a

macrolide Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural products. ...

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

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.