Ragulator complex protein LAMTOR1 (LAMTOR1)
The protein contains 161 amino acids for an estimated molecular weight of 17745 Da.
As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. LAMTOR1 is directly responsible for anchoring the Ragulator complex to membranes. Also required for late endosomes/lysosomes biogenesis it may regulate both the recycling of receptors through endosomes and the MAPK signaling pathway through recruitment of some of its components to late endosomes. May be involved in cholesterol homeostasis regulating LDL uptake and cholesterol release from late endosomes/lysosomes. May also play a role in RHOA activation. (updated: March 4, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.
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| Variant | Description |
|---|---|
| dbSNP:rs1053443 |
Biological Process
Cell cycle arrest
Cell growth
Cellular protein localization
Cellular response to amino acid starvation
Cellular response to amino acid stimulus
Cholesterol homeostasis
Endosomal transport
Endosome localization
Endosome organization
Lysosome localization
Lysosome organization
Neutrophil degranulation
Positive regulation of GTPase activity
Positive regulation of MAPK cascade
Positive regulation of TOR signaling
Regulation of catalytic activity
Regulation of cell growth
Regulation of cholesterol efflux
Regulation of cholesterol esterification
Regulation of cholesterol import
Regulation of macroautophagy
Regulation of molecular function
Regulation of receptor recycling
The reference OMIM entry for this protein is 613510
Late endosomal/lysosomal adaptor, mitogen-activated protein kinase and mammalian target of rapamycin activator 1; lamtor1
Late endosomal/lysosomal adaptor, mapk and mtor activator 1
P27(kip1)-releasing factor from rhoa; p27rf-rho
Protein associ
DESCRIPTION
LAMTOR1 is part of a lysosomal complex that senses amino acid availability and induces MTOR (601231) signaling in response to amino acids (Rebsamen et al., 2015).CLONING
Hoshino et al. (2009) stated that C11ORF59, which they called p27RF-Rho, was first identified as a protein that copurified with matrix metalloproteinase-1 (MMP1; 120353) from a human melanoma cell line. The 161-amino acid protein contains 1 myristoylation and 2 palmitoylation sites at its N terminus. Northern blot analysis detected variable expression of p27RF-Rho mRNA in all human tissues examined. Orthologs of p27RF-Rho were identified in a number of vertebrate species. p27RF-Rho localized to a punctate distribution in a human fibrosarcoma cell line, and Western blot analysis detected p27RF-Rho at an apparent molecular mass of 17 kD. Using mass spectrometry to identify proteins that purified with detergent-resistant membranes from SHEP human neuroblastoma cells, followed by RT-PCR, Guillaumot et al. (2010) cloned C11ORF59, which they called PDRO. The deduced 161-amino acid protein contains a dileucine motif near its N-terminal end in addition to the N-terminal myristoylation and palmitoylation sites. Confocal microscopy showed that fluorescence-tagged PDRO localized to ring-shaped structures that also expressed markers of late endosomes and lysosomes.GENE FUNCTION
RhoA (165390) is a small GTPase that has a pivotal role in regulating the organization of the actin cytoskeleton. Using knockdown and overexpression studies, Hoshino et al. (2009) found that p27RF-Rho enhanced the activation of RhoA by releasing it from inhibition by cytoplasmic p27(Kip1) (CDKN1B; 600778) in human cell lines. p27RF-Rho bound and sequestered p27(Kip1), allowing RhoA to be activated by its guanine nucleotide exchange factors (see ARHGEF1, 601855), initiating cell motility and invasiveness. Using mutation analysis, Guillaumot et al. (2010) showed that the myristoylation and palmitoylation sites of PDRO were required to target PDRO to detergent-resistant membranes in vitro and to perinuclear late endosomes and lysosomes in intact SHEP cells. Expression of PDRO mRNA and protein was upregulated by depletion of cellular cholesterol and downregulated by cholesterol loading. Knockdown of PDRO via small interfering RNA increased cellular free cholesterol content, which was due, at least in part, to elevated uptake of low-density lipoprotein and cholesterol egress from late endosomes and lysosomes. PDRO-knockdown cells also displayed elevated cholesterol efflux. Conversely, overexpression of PDRO reduced cellular free cholesterol content. Guillaumot et al. (2010) concluded that PDRO is involved in cellular cholesterol homeostasis, which may be linked to its role in regulating the actin cytoskeleton. Using tandem affinity purification, chromatography, and mass spectrometric analysis of HEK293 cells, Rebsamen et al. (2015) identified a lysosomal supercomplex that included all 5 members of the Ragulator/LAMTOR complex, including LAMTOR1, and all 4 RAG GTPases (see RRAGA, 612194). The complex also included RAPTOR (607130), which is involved in nutrient sensing by MTOR complex-1, and the amino acid transporter SLC38A9 (616203).GENE STRUCTURE
Guillaumot et al. (2010) identified 5 putative sterol response elements in the upstream region of the C11ORF59 gene.MAPPING
By genomic sequence analysis, Guillaumot et al. (2010) mapped the C11ORF59 ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 613510 was added.