Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1)
The protein contains 522 amino acids for an estimated molecular weight of 59123 Da.
Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Within mTORC2, MAPKAP1 is required for complex formation and mTORC2 kinase activity. MAPKAP1 inhibits MAP3K2 by preventing its dimerization and autophosphorylation. Inhibits HRAS and KRAS signaling. Enhances osmotic stress-induced phosphorylation of ATF2 and ATF2-mediated transcription. Involved in ciliogenesis, regulates cilia length through its interaction with CCDC28B independently of mTORC2 complex. (updated: Sept. 12, 2018)
Protein identification was indicated in the following studies:
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- 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.
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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Biological Process
Activation of protein kinase B activity
Establishment or maintenance of actin cytoskeleton polarity
Negative regulation of Ras protein signal transduction
Positive regulation of peptidyl-serine phosphorylation
Regulation of cellular response to oxidative stress
Regulation of signal transduction by p53 class mediator
Substantia nigra development
TORC2 signaling
Cellular Component
Cytoplasm
Cytoplasmic vesicle
Cytosol
Golgi apparatus
Nucleoplasm
Plasma membrane
TORC2 complex
The reference OMIM entry for this protein is 610558
Mitogen-activated protein kinase-associated protein 1; mapkap1
Sapk-interacting protein 1; sin1
Mekk2-interacting protein 1; mip1
Jc310
DESCRIPTION
SIN1, MTOR (FRAP1; 601231), RICTOR (609022), and LST8 (GBL; 612190) are components of TORC2, a protein kinase complex involved in AKT (164730) phosphorylation and cell signaling (Yang et al., 2006).CLONING
By screening an expression library for cDNAs that suppressed the heat shock-sensitive phenotype of yeast with an activated Ras2 gene (see HRAS; 190020), Colicelli et al. (1991) obtained a partial cDNA encoding MAPKAP1, which they called JC310. By searching an EST database with the partial JC310 sequence, followed by RT-PCR, Schroder et al. (2004) obtained a full-length cDNA encoding MAPKAP1, which they called SIN1. The deduced 522-amino acid protein has a nuclear localization signal, 2 bipartite nuclear localization signals, a peroxisomal targeting signal, and a PEST motif for rapid protein degradation. Comparison of SIN1 with homologs from various species revealed a short, highly conserved region, designated Box1, located within a larger conserved domain, designated CRIM (conserved region in middle). Schroder et al. (2004) also identified several SIN1 splice variants, including SIN1-alpha, which encodes a 323-amino acid C-terminally truncated protein, and SIN1-beta and SIN1-gamma, which encode 487- and 475-amino acid proteins, respectively, with internal deletions. Two other variants, SIN1-delta and SIN1-epsilon, lack the first coding exon and the first 2 coding exons of SIN1, respectively. Northern blot analysis detected SIN1 transcripts of 3.8 and 2.6 kb in all tissues examined, with highest levels in skeletal muscle and heart.GENE FUNCTION
Yang et al. (2006) identified SIN1 as an essential component of TORC2, but not TORC1. SIN1 specifically interacted with MTOR and RICTOR, but not RAPTOR (607130), the defining component of the TORC1 complex. Knockdown of SIN1 resulted in decreased RICTOR phosphorylation and protein levels, as well as disruption of binding between RICTOR and MTOR. RICTOR knockdown dramatically decreased SIN1 protein levels. Knockdown of SIN1 in both Drosophila and human cells diminished AKT phosphorylation, and SIN1-knockdown cells displayed less phosphorylation of AKT substrates and more sensitivity to apoptosis. Independently, Jacinto et al. (2006) identified SIN1 as an essential TORC2 subunit in human cells. Phosphorylation of Akt at ser473 was lost in Sin1 -/- mouse embryonic fibroblasts (MEFs), whereas phosphorylation of thr308 was unaffected. Defective ser473 phosphorylation affected only a subset of Akt targets in vivo, including Foxo1 (136533) and Foxo3a (602681). Sin1 -/- MEFs were more sensitive to stress-induced apoptosis, suggesting that phosphorylation of AKT at ser473 plays an important role in cell survival.GENE STRUCTURE
Schroder et al. (2004) determined that the MAPKAP1 gene contains 13 exons, the first of which is noncoding. The 5-prime region contains 2 short open reading frames of 9 and 5 codons, and the 3-prime region contains 2 polyadenylation sites.MAPPING
The International Radiation Hybrid Mapping Consortium mapped the MAPKAP1 gene to chromosome 9 (TMAP RH41772).ANIMAL MODEL
Jacinto et al. (2006) found that Sin1 deletion was embryonic lethal in mice due to early developmental problems. ... More on the omim web site
June 30, 2020: Protein entry updated
Automatic update: OMIM entry 610558 was added.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).