Alternative titles; symbols
HGNC Approved Gene Symbol: CASTOR2
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38): 7:74,964,705-75,031,528 (from NCBI)
The GATOR1 and GATOR2 complexes regulate amino acid sensing for mTOR complex-1 (mTORC1; see 601231), a master growth regulator that integrates diverse environmental inputs to coordinate anabolic and catabolic processes. GATSL2 and GATSL3 (617034) form homodimers and heterodimers that interact with GATOR2 and negatively regulate mTORC1 activity (Chantranupong et al., 2016).
Chantranupong et al. (2016) reported that the deduced 329-amino acid GATSL2 protein, which they called CASTOR2, has 2 ACT domains, which are predicted to bind small molecules such as amino acids. CASTOR2 shares 63% amino acid identity with CASTOR1 (GATSL3). Database analysis indicated low CASTOR2 expression in most human tissues, with higher expression in skeletal muscle only. Orthologs of CASTOR1 and CASTOR2 were detected in vertebrates, and a single ortholog was detected in some invertebrates, such as sea urchins and sea anemones, but orthologs were not found in yeast, C. elegans, or Drosophila.
By database analysis, Chantranupong et al. (2016) found that CASTOR2 likely interacted with CASTOR1. Immunoprecipitation and Western blot analysis of HEK293T cells showed interaction between CASTOR2 and the GATOR2 subunit MIOS (615359). CASTOR1 and CASTOR2 robustly interacted with themselves and with each other to form homo- and heterooligomers in a 1:1 ratio. Arginine bound to CASTOR1, but not CASTOR2, and CASTOR1-CASTOR2 dimers bound roughly half as much arginine as CASTOR1 homodimers. Arginine disrupted interaction between the GATOR2 complex and CASTOR1 homodimers or CASTOR1-CASTOR2 heterodimers, but it had no effect on interaction between GATOR2 and CASTOR2 homodimers. Consequently, CASTOR2 homodimers inhibited mTORC1 activity in an arginine-independent manner. In the presence of arginine, overexpression of CASTOR2 reduced maximal arginine-induced mTORC1 activity. Chantranupong et al. (2016) concluded that CASTOR2 constitutively associates with GATOR2 to dampen mTORC1 signaling.
Hartz (2016) mapped the GATSL2 gene to chromosome 7q11.23 based on an alignment of the GATSL2 sequence (GenBank BC147030) with the genomic sequence (GRCh38).
Chantranupong, L., Scaria, S. M., Saxton, R. A., Gygi, M. P., Shen, K., Wyant, G. A., Wang, T., Harper, J. W., Gygi, S. P., Sabatini, D. M. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165: 153-164, 2016. [PubMed: 26972053] [Full Text: https://doi.org/10.1016/j.cell.2016.02.035]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/13/2016.