Alternative titles; symbolsAVO3, S. CEREVISIAE, HOMOLOG OF; AVO3KIAA1999HGNC Approved Gene Symbol: RICTORCytogenetic location: 5p13.1 Genomic coordinates (GR...
Alternative titles; symbols
HGNC Approved Gene Symbol: RICTOR
Cytogenetic location: 5p13.1 Genomic coordinates (GRCh38): 5:38,937,919-39,074,420 (from NCBI)
RICTOR and MTOR (FRAP1; 601231) are components of a protein complex that integrates nutrient- and growth factor-derived signals to regulate cell growth (Sarbassov et al., 2004).
▼ Cloning and Expression
By sequencing clones obtained from a size-fractionated brain cDNA library, Ohara et al. (2002) cloned KIAA1999. RT-PCR ELISA detected intermediate and relatively uniform expression in all adult and fetal tissues and specific brain regions examined.
By sequencing peptides obtained from purified human RICTOR, followed by database analysis and RT-PCR, Sarbassov et al. (2004) cloned RICTOR cDNA. The deduced 1,708-amino acid protein has a calculated molecular mass of 192 kD. RICTOR contains evolutionarily conserved sequences, notably an N-terminal region of about 200 amino acids and several smaller regions, including a repeated block of 20 amino acids.
Jacinto et al. (2004) cloned mouse Rictor, which they called Avo3. The deduced protein contains 1,708 amino acids. A 9.5-kb transcript was detected in all tissues examined, with higher levels in skeletal muscle, kidney, placenta, and leukocytes.
▼ Gene Function
Sarbassov et al. (2004) found that there was an inverse correlation between the relative amounts of RAPTOR (607130) and RICTOR in several human cell lines. Rapamycin treatment of human embryonic kidney cells eliminated the binding of MTOR to RAPTOR, but did not affect the interaction of MTOR with RICTOR. Knockdown of RICTOR caused accumulation of thick actin fibers throughout much of the cytoplasm in HeLa cells, loss of actin at the cell cortex, altered distribution of cytoskeletal proteins, and reduced protein kinase C (PKC)-alpha (see 176960) activity. Sarbassov et al. (2004) found that the RICTOR-containing MTOR complex contains LST8 (GBL; 612190) but not RAPTOR. Furthermore, the RICTOR-MTOR complex did not regulate the MTOR effector S6K1 (608938) and was not bound by FKBP12 (186945)-rapamycin. Sarbassov et al. (2004) concluded that the RICTOR-MTOR complex modulates the phosphorylation of PKC-alpha and the actin cytoskeleton, similar to TOR signaling in yeast.
Jacinto et al. (2004) identified 2 distinct mammalian TOR complexes: TORC1, which contains TOR, LST8, and RAPTOR, and TORC2, which contains TOR, LST8, and RICTOR. Like yeast TORC2, mammalian TORC2 was rapamycin insensitive and functioned upstream of Rho GTPases to regulate the actin cytoskeleton. TORC2 did not regulate S6K activity. Knockdown of TORC2, but not TORC1, prevented paxillin (602505) phosphorylation, actin polymerization, and cell spreading.
Akt/PKB (164730) activation requires the phosphorylation of ser473. Sarbassov et al. (2005) showed that in Drosophila and in human cells TOR (FRAP1; 601231) and its associated protein rictor are necessary for ser473 phosphorylation, and that a reduction in rictor or mTOR expression inhibited an AKT/PKB effector. The rictor-mTOR complex directly phosphorylated Akt/PKB on ser473 in vitro and facilitated thr308 phosphorylation by PDK1 (605213).
By genomic sequence analysis, Ohara et al. (2002) mapped the RICTOR gene to chromosome 5.
Stumpf (2022) mapped the RICTOR gene to chromosome 5p13.1 based on an alignment of the RICTOR sequence (GenBank BC137163) with the genomic sequence (GRCh38).
▼ Animal Model
Yang et al. (2006) found that Rictor knockout in mice was embryonic lethal. Rictor -/- embryos had no detectable Akt phosphorylation on ser473 and greatly reduced Akt phosphorylation on thr308. Western blot analysis showed that phosphorylation of multiple Akt substrates was decreased in Rictor -/- embryos. Yang et al. (2006) concluded that TORC2 plays a critical role in AKT activation.
By analysis of Rictor-null mouse embryos, Shiota et al. (2006) found that Rictor was critical for Akt phosphorylation during embryogenesis, and that it was essential for normal growth and development. Rictor-null mouse fibroblasts exhibited low proliferation rates, impaired Akt activity, and diminished metabolic activity.
Lee et al. (2010) found that mice with a conditional deletion of Rictor, an essential component of TORC2, exhibited impaired differentiation into Th1 and Th2 cells but retained Th17 cell generation. Immunoblot analysis of activated Cd4 (186940)-positive T cells revealed reduced phosphorylation of Akt and Pkc. In Rictor-deficient cells, complementation with active Akt restored only Tbet (TBX21; 604895) expression and Th1 cell differentiation, whereas activated Pkc-theta (PRKCQ; 600448) reverted only Gata3 (131320) transcription and Th2 cell defects. Lee et al. (2010) concluded that the dominant function of TORC2 under physiologic conditions in T cells is to guide differentiation mediated dichotomously by the TORC2 targets AKT and PKC.
Zhao et al. (2014) disrupted TORC2 through deletion of Rictor in heart and observed normal heart growth and function. Rictor deletion caused significant reduction of Akt ser473 phosphorylation and enhanced thr308 phosphorylation, indicating that the latter maintains Akt activity and heart function. Deletion of Pdk1 in heart caused enhanced Akt ser473 phosphorylation that was suppressed by deletion of Rictor, leading to worsened dilated cardiomyopathy and accelerated heart failure in Pdk1-deficient mice. Increased Akt ser473 phosphorylation via genetic or chemical ablation of Pten (601728) reversed dilated cardiomyopathy and heart failure in Pdk1-deficient mice. Humans with dilated cardiomyopathy also had changes in PDK1 and AKT ser473 phosphorylation levels similar to those observed in the mouse models, suggesting that impairment of PDK1-AKT signaling causes dilated cardiomyopathy in humans. Zhao et al. (2014) concluded that Pdk1 and TORC2 synergistically promote postnatal heart growth and maintain heart function in postnatal mice.