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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 (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. 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.


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 In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
,
lysosomes A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prote ...
, and cytoplasmic granules. Amino acid availability determines RPTOR targeting to lysosomes. In stressed cells, RPTOR associates with
SPAG5 Sperm-associated antigen 5 is a protein that in humans is encoded by the ''SPAG5'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' ...
and accumulates in stress granules, which significantly reduces its presence in
lysosomes A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prote ...
.


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 The mammalian target of 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 ''MTOR'' gene. ...
pathway. The adapter protein and
mTOR The mammalian target of 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 ''MTOR'' gene. ...
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 The mammalian target of 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 ''MTOR'' gene. ...
kinase. RPTOR also has a positive role in maintaining cell size and
mTOR The mammalian target of 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 ''MTOR'' gene. ...
protein expression. The association of
mTOR The mammalian target of 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 ''MTOR'' gene. ...
and RPTOR is stabilized by nutrient deprivation and other conditions which suppress the
mTOR The mammalian target of 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 ''MTOR'' gene. ...
pathway. Multiple transcript variants exist for this gene which encode different isoforms.


Structure

RPTOR is a 150 kDa
mTOR The mammalian target of 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 ''MTOR'' gene. ...
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 compo ...
). This complex contains
mTOR The mammalian target of 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 ''MTOR'' gene. ...
,
MLST8 Target of rapamycin complex subunit LST8, also known as mammalian lethal with SEC13 protein 8 (mLST8) or TORC subunit LST8 or G protein beta subunit-like (GβL or Gable), is a protein that in humans is encoded by the ''MLST8'' (MTOR associated pro ...
, RPTOR,
AKT1S1 Proline-rich AKT1 substrate 1 (PRAS) is a protein that in humans is encoded by the ''AKT1S1'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''ge ...
/PRAS40, and DEPTOR.
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 compo ...
both binds to and is inhibited by FKBP12-rapamycin.
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 compo ...
activity is upregulated by
mTOR The mammalian target of 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 ''MTOR'' gene. ...
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 AMPK may refer to: * AMP-activated protein kinase 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate gl ...
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
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 compo ...
complex.
RPS6KA1 Ribosomal protein S6 kinase alpha-1 is an enzyme that in humans is encoded by the ''RPS6KA1'' gene. Function This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 nonidentical k ...
stimulates
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 compo ...
activity by phosphorylating at Ser-719, Ser-721, and Ser-722 as a response to growth factors.


Interactions

*
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 compo ...
binds to and is inhibited by FKBP12-rapamycin * RPTOR binds to 4EBP1 and RPS6KB1 directly whether or not it is associated with
mTOR The mammalian target of 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 ''MTOR'' gene. ...
* RPTOR binds to poorly phosphorylated or non-phosphorylated
EIF4EBP1 Eukaryotic translation initiation factor 4E-binding protein 1 (also known as 4E-BP1) is a protein that in humans is encoded by the ''EIF4EBP1'' gene. Function This gene encodes one member of a family of translation repressor proteins. The prot ...
preferentially, which is important for
mTOR The mammalian target of 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 ''MTOR'' gene. ...
to be able to catalyze phosphorylation. * RPTOR interacts with
ULK1 ULK1 is an enzyme that in humans is encoded by the ''ULK1'' gene. Unc-51 like autophagy activating kinase (ULK1/2) are two similar isoforms of an enzyme that in humans are encoded by the ''ULK1/2'' genes. .html" ;"title="/sup>">/sup> .html" ;"t ...
. This interaction depends on nutrients and is reduced in the case of starvation. * When RPTOR is phosphorylated by
AMPK AMPK may refer to: * AMP-activated protein kinase 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate gl ...
, it interacts with 14-3-3 protein and inhibits its activity. * RPTOR interacts with
SPAG5 Sperm-associated antigen 5 is a protein that in humans is encoded by the ''SPAG5'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' ...
, which competes with
mTOR The mammalian target of 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 ''MTOR'' gene. ...
for binding RPTOR and causes decreased
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 compo ...
formation. * RPTOR interacts with
G3BP1 Ras GTPase-activating protein-binding protein 1 is an enzyme that in humans is encoded by the ''G3BP1'' gene. This gene encodes one of the DNA-unwinding enzymes which prefers partially unwound 3'-tailed substrates and can also unwind partial RNA/ ...
. Oxidative stress increases the formation of the complex formed with RPTOR,
G3BP1 Ras GTPase-activating protein-binding protein 1 is an enzyme that in humans is encoded by the ''G3BP1'' gene. This gene encodes one of the DNA-unwinding enzymes which prefers partially unwound 3'-tailed substrates and can also unwind partial RNA/ ...
, and
SPAG5 Sperm-associated antigen 5 is a protein that in humans is encoded by the ''SPAG5'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' ...
RPTOR has also been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
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 PIP3 ...
* RHEB, *
RICTOR Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the ''RICTOR'' gene. RICTOR and mTOR are components of a protein complex that integrates nutrient- and growth factor-derived s ...
, and *
mammalian target of rapamycin The mammalian target of 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 ''MTOR'' gene. ...
(mTOR),


Clinical significance


Signaling in cancer

The clinical significance of RPTOR is primarily due to its involvement in the
mTOR The mammalian target of 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 ''MTOR'' gene. ...
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 The mammalian target of 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 ''MTOR'' gene. ...
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 Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid th ...
).
PIP3 Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid th ...
is a membrane-docking site for
AKT Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...
and
PDK1 Pyruvate dehydrogenase lipoamide kinase isozyme 1, mitochondrial is an enzyme that in humans is encoded by the ''PDK1'' gene. It codes for an isozyme of pyruvate dehydrogenase kinase (PDK). Pyruvate dehydrogenase (PDH) is a part of a mitochondri ...
. In turn, active
PDK1 Pyruvate dehydrogenase lipoamide kinase isozyme 1, mitochondrial is an enzyme that in humans is encoded by the ''PDK1'' gene. It codes for an isozyme of pyruvate dehydrogenase kinase (PDK). Pyruvate dehydrogenase (PDH) is a part of a mitochondri ...
, along with
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 compo ...
, phosphorylates S6K in the part of the
mTOR The mammalian target of 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 ''MTOR'' gene. ...
pathway which promotes protein synthesis and cell growth. The
mTOR The mammalian target of 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 ''MTOR'' gene. ...
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 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 compo ...
. mTORC1 phosphorylates Atg13 and stops it from forming the ULK1 kinase complex. This inhibits autophagy, the major degradation pathway in eukaryotic cells. Because
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 compo ...
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. The
mTOR The mammalian target of 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 ''MTOR'' gene. ...
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 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 compo ...
association and preventing apoptosis induced by
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 compo ...
hyperactivation. Because astrin is frequently upregulated in tumors, it is a potential target to sensitize tumors to apoptosis through the
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 compo ...
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 The mammalian target of 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 ''MTOR'' gene. ...
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 transplant rejection, treat a rare lung disease called lymphangioleiomyomatosi ...
. However, the complex
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 compo ...
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 transplant rejection, treat a rare lung disease called lymphangioleiomyomatosi ...
.
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 transplant rejection, treat a rare lung disease called lymphangioleiomyomatosi ...
is a
macrolide The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...
which is an immunosuppressant in humans that inhibits
mTOR The mammalian target of 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 ''MTOR'' gene. ...
by binding to its intracellular receptor
FKBP12 Peptidyl-prolyl cis-trans isomerase FKBP1A is an enzyme that in humans is encoded by the ''FKBP1A'' gene. Function The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basi ...
. In many cancers, hyperactive
AKT Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...
signaling leads to increased
mTOR The mammalian target of 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 ''MTOR'' gene. ...
signaling, so
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 transplant rejection, treat a rare lung disease called lymphangioleiomyomatosi ...
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.


See also

*
RICTOR Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the ''RICTOR'' gene. RICTOR and mTOR are components of a protein complex that integrates nutrient- and growth factor-derived s ...
*
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 compo ...


References


Further reading

* * * * * * * * * * * * * * * {{KIAA human genes Genes on human chromosome 3