UniProt functional annotation for Q92574



	UniProt functional annotation for Q92574

UniProt code: Q92574.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: In complex with TSC2, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400). Seems not to be required for TSC2 GAP activity towards RHEB (PubMed:15340059). Implicated as a tumor suppressor. Involved in microtubule-mediated protein transport, but this seems to be due to unregulated mTOR signaling (By similarity). Acts as a co- chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1 (PubMed:29127155). Increases ATP binding to HSP90AA1 and inhibits HSP90AA1 ATPase activity (PubMed:29127155). Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:29127155). Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and ubiquitin ligase HERC1 (PubMed:16464865, PubMed:29127155). {ECO:0000250|UniProtKB:Q9Z136, ECO:0000269|PubMed:12271141, ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:16464865, ECO:0000269|PubMed:28215400, ECO:0000269|PubMed:29127155}.

Subunit: Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex (PubMed:29127155). Interacts (via C-terminus) with the closed form of HSP90AA1 (via the middle domain and TPR repeat- binding motif) (PubMed:29127155). Interacts with TSC2; the interaction stabilizes TSC2 and prevents TSC2 self-aggregation (PubMed:10585443, PubMed:15963462, PubMed:16464865, PubMed:9580671, PubMed:9809973, PubMed:29127155, PubMed:28215400). Interacts with DOCK7 (PubMed:15963462). Interacts with FBXW5 (PubMed:18381890). Interacts with TBC1D7 (PubMed:17658474). Interacts with WDR45B (PubMed:28561066). Interacts with RPAP3 and URI1 (PubMed:28561026). {ECO:0000269|PubMed:10585443, ECO:0000269|PubMed:15963462, ECO:0000269|PubMed:16464865, ECO:0000269|PubMed:17658474, ECO:0000269|PubMed:18381890, ECO:0000269|PubMed:28215400, ECO:0000269|PubMed:28561026, ECO:0000269|PubMed:28561066, ECO:0000269|PubMed:29127155, ECO:0000269|PubMed:9580671, ECO:0000269|PubMed:9809973}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:9809973}. Membrane {ECO:0000269|PubMed:9809973}; Peripheral membrane protein {ECO:0000269|PubMed:9809973}. Note=At steady state found in association with membranes. {ECO:0000269|PubMed:9809973}.

Tissue specificity: Highly expressed in skeletal muscle, followed by heart, brain, placenta, pancreas, lung, liver and kidney. Also expressed in embryonic kidney cells.

Domain: The C-terminal putative coiled-coil domain is necessary for interaction with TSC2. {ECO:0000269|PubMed:9580671}.

Ptm: Phosphorylation at Ser-505 does not affect interaction with TSC2. {ECO:0000269|PubMed:15963462}.

Disease: Tuberous sclerosis 1 (TSC1) [MIM:191100]: An autosomal dominant multi-system disorder that affects especially the brain, kidneys, heart, and skin. It is characterized by hamartomas (benign overgrowths predominantly of a cell or tissue type that occurs normally in the organ) and hamartias (developmental abnormalities of tissue combination). Clinical manifestations include epilepsy, learning difficulties, behavioral problems, and skin lesions. Seizures can be intractable and premature death can occur from a variety of disease- associated causes. {ECO:0000269|PubMed:10227394, ECO:0000269|PubMed:10533069, ECO:0000269|PubMed:10570911, ECO:0000269|PubMed:10874311, ECO:0000269|PubMed:11829138, ECO:0000269|PubMed:18830229, ECO:0000269|PubMed:22161988, ECO:0000269|PubMed:9328481}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Lymphangioleiomyomatosis (LAM) [MIM:606690]: Progressive and often fatal lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. It affects almost exclusively young women and can occur as an isolated disorder or in association with tuberous sclerosis complex. {ECO:0000269|PubMed:11829138}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Focal cortical dysplasia 2 (FCORD2) [MIM:607341]: 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. {ECO:0000269|PubMed:28215400}. Note=The disease is caused by variants affecting the gene represented in this entry.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		In complex with TSC2, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400). Seems not to be required for TSC2 GAP activity towards RHEB (PubMed:15340059). Implicated as a tumor suppressor. Involved in microtubule-mediated protein transport, but this seems to be due to unregulated mTOR signaling (By similarity). Acts as a co- chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1 (PubMed:29127155). Increases ATP binding to HSP90AA1 and inhibits HSP90AA1 ATPase activity (PubMed:29127155). Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:29127155). Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and ubiquitin ligase HERC1 (PubMed:16464865, PubMed:29127155). {ECO:0000250\|UniProtKB:Q9Z136, ECO:0000269\|PubMed:12271141, ECO:0000269\|PubMed:15340059, ECO:0000269\|PubMed:16464865, ECO:0000269\|PubMed:28215400, ECO:0000269\|PubMed:29127155}.


Subunit:		Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex (PubMed:29127155). Interacts (via C-terminus) with the closed form of HSP90AA1 (via the middle domain and TPR repeat- binding motif) (PubMed:29127155). Interacts with TSC2; the interaction stabilizes TSC2 and prevents TSC2 self-aggregation (PubMed:10585443, PubMed:15963462, PubMed:16464865, PubMed:9580671, PubMed:9809973, PubMed:29127155, PubMed:28215400). Interacts with DOCK7 (PubMed:15963462). Interacts with FBXW5 (PubMed:18381890). Interacts with TBC1D7 (PubMed:17658474). Interacts with WDR45B (PubMed:28561066). Interacts with RPAP3 and URI1 (PubMed:28561026). {ECO:0000269\|PubMed:10585443, ECO:0000269\|PubMed:15963462, ECO:0000269\|PubMed:16464865, ECO:0000269\|PubMed:17658474, ECO:0000269\|PubMed:18381890, ECO:0000269\|PubMed:28215400, ECO:0000269\|PubMed:28561026, ECO:0000269\|PubMed:28561066, ECO:0000269\|PubMed:29127155, ECO:0000269\|PubMed:9580671, ECO:0000269\|PubMed:9809973}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:9809973}. Membrane {ECO:0000269\|PubMed:9809973}; Peripheral membrane protein {ECO:0000269\|PubMed:9809973}. Note=At steady state found in association with membranes. {ECO:0000269\|PubMed:9809973}.
Tissue specificity:		Highly expressed in skeletal muscle, followed by heart, brain, placenta, pancreas, lung, liver and kidney. Also expressed in embryonic kidney cells.
Domain:		The C-terminal putative coiled-coil domain is necessary for interaction with TSC2. {ECO:0000269\|PubMed:9580671}.
Ptm:		Phosphorylation at Ser-505 does not affect interaction with TSC2. {ECO:0000269\|PubMed:15963462}.
Disease:		Tuberous sclerosis 1 (TSC1) [MIM:191100]: An autosomal dominant multi-system disorder that affects especially the brain, kidneys, heart, and skin. It is characterized by hamartomas (benign overgrowths predominantly of a cell or tissue type that occurs normally in the organ) and hamartias (developmental abnormalities of tissue combination). Clinical manifestations include epilepsy, learning difficulties, behavioral problems, and skin lesions. Seizures can be intractable and premature death can occur from a variety of disease- associated causes. {ECO:0000269\|PubMed:10227394, ECO:0000269\|PubMed:10533069, ECO:0000269\|PubMed:10570911, ECO:0000269\|PubMed:10874311, ECO:0000269\|PubMed:11829138, ECO:0000269\|PubMed:18830229, ECO:0000269\|PubMed:22161988, ECO:0000269\|PubMed:9328481}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Lymphangioleiomyomatosis (LAM) [MIM:606690]: Progressive and often fatal lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. It affects almost exclusively young women and can occur as an isolated disorder or in association with tuberous sclerosis complex. {ECO:0000269\|PubMed:11829138}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Focal cortical dysplasia 2 (FCORD2) [MIM:607341]: 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. {ECO:0000269\|PubMed:28215400}. Note=The disease is caused by variants affecting the gene represented in this entry.