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MTOR phospho T2446

Domain

The kinase domain (PI3K/PI4K) is intrinsically active but has a highly restricted catalytic center.

The FAT domain forms three discontinuous subdomains of alpha-helical TPR repeats plus a single subdomain of HEAT repeats. The four domains pack sequentially to form a C-shaped a-solenoid that clamps onto the kinase domain (PubMed:23636326).

Function

The protein expressed by the MTOR gene is a serine/threonine protein kinase that serves as a central regulator of cellular metabolism, growth, and survival in response to various signals, such as hormones and nutrients. MTOR operates within two distinct signaling complexes, mTORC1 and mTORC2. mTORC1 is activated to upregulate protein synthesis by phosphorylating regulators of mRNA translation and ribosome synthesis, and phosphorylates and activates proteins like RPS6KB1 and RPS6KB2 to promote protein synthesis. It controls MiT/TFE factors TFEB and TFE3 by mediating their retention and inactivation under nutrient-rich conditions, and it inhibits autophagy by phosphorylating DAP and RUBCNL/Pacer. Additionally, mTORC1 engages in feedback control on growth factor signaling and may influence microtubules through CLIP1 phosphorylation. The mTORC2 complex may regulate cellular processes, including survival and cytoskeletal organization, by phosphorylating AKT1 and regulating the actin cytoskeleton via PRKCA, PXN, and Rho-type guanine nucleotide exchange factors. It also regulates the phosphorylation of SGK1. This supplementary information is collated from multiple sources and compiled automatically.

Involvement in disease

Smith-Kingsmore syndrome

SKS

An autosomal dominant syndrome characterized by intellectual disability, macrocephaly, seizures, umbilical hernia, and facial dysmorphic features.

None

The disease is caused by variants affecting the gene represented in this entry.

Focal cortical dysplasia 2

FCORD2

A form of focal cortical dysplasia, a malformation of cortical development that results in medically refractory epilepsy in the pediatric population and in adults. FCORD2 is a severe form, with onset usually in childhood, characterized by disrupted cortical lamination and specific cytological abnormalities. It is classified in 2 subtypes: type IIA characterized by dysmorphic neurons and lack of balloon cells; type IIB with dysmorphic neurons and balloon cells.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Autophosphorylates when part of mTORC1 or mTORC2 (PubMed:15467718, PubMed:9434772). Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes autophosphorylation (PubMed:19487463). Phosphorylation in the kinase domain modulates the interactions of MTOR with RPTOR and AKT1S1/PRAS40 and leads to increased intrinsic mTORC1 kinase activity (PubMed:15905173, PubMed:19145465, PubMed:21576368). Phosphorylation at Ser-2159 by TBK1 in response to growth factors and pathogen recognition receptors promotes mTORC1 activity (PubMed:29150432). Phosphorylation at Thr-2173 in the ATP-binding region by AKT1 strongly reduces kinase activity (PubMed:24247430).

Sequence Similarities

Belongs to the PI3/PI4-kinase family.

Tissue Specificity

Expressed in numerous tissues, with highest levels in testis.

Cellular localization

Alternative names

FRAP, FRAP1, FRAP2, RAFT1, RAPT1, MTOR, Serine/threonine-protein kinase mTOR, FK506-binding protein 12-rapamycin complex-associated protein 1, FKBP12-rapamycin complex-associated protein, Mammalian target of rapamycin, Mechanistic target of rapamycin, Rapamycin and FKBP12 target 1, Rapamycin target protein 1, mTOR

swissprot:P42345

Other research areas