HGNC Approved Gene Symbol: RASAL3
Cytogenetic location: 19p13.12 Genomic coordinates (GRCh38): 19:15,451,624-15,464,544 (from NCBI)
RAS GTPase-activating proteins (RASGAPs) negatively regulate the RAS (190020)/ERK (see 601795) signaling pathway and have crucial roles in proliferation, function, and development of various cell types. RASAL3 is a RASGAP that is predominantly expressed in hematopoietic cells (Saito et al., 2015).
Saito et al. (2015) cloned RASAL3 from a human T-cell line. Like other RASAL family members (e.g., RASAL1; 604118), the deduced 1,011-amino acid RASAL3 protein has pleckstrin (PLEK; 173570) homology (PH), C2, and RASGAP domains. RT-PCR analysis detected Rasal3 expression predominantly in mouse thymus, spleen, blood, and bone marrow, particularly in T cells and natural killer T (NKT) cells. Western blot analysis showed expression of a 112-kD protein in human hemopoietic cell lines. Immunofluorescence microscopy demonstrated cytoplasmic expression of RASAL3 near the plasma membrane in 293T cells.
Gross (2015) mapped the RASAL3 gene to chromosome 19p13.12 based on an alignment of the RASAL3 sequence (GenBank BC030281) with the genomic sequence (GRCh38).
Saito et al. (2015) found that knockdown of RASAL3 via short hairpin RNA increased expression of phosphorylated ERK, a marker of RAS activation, in a human B-cell line. However, the increase in phosphorylated ERK was only weak in a human T-cell line following RASAL3 knockdown.
Using flow cytometric analysis, Saito et al. (2015) demonstrated reduced numbers of T cells and, particularly, NKT cells in liver, but not spleen, of Rasal3 -/- mice. Thymic NKT cell development was normal in Rasal3 -/- mice, and Rasal3 -/- NKT cell expression of Cxcr6 (605163) and Lfa1 (see 153370) was equivalent to wildtype cells. Injection of alpha-GalCer, a specific ligand for NKT cells, resulted in reduced cytokine production in Rasal3 -/- mice compared with wildtype mice. Liver injury induced by alpha-GalCer was also attenuated in Rasal3 -/- mice compared with wildtype. NKT cells from Rasal3 -/- liver expressed reduced amounts of phosphorylated Erk. Saito et al. (2015) concluded that RASAL3 plays an important role in expansion and function of liver NKT cells by negatively regulating RAS/ERK signaling.
Gross, M. B. Personal Communication. Baltimore, Md. 9/18/2015.
Saito, S., Kawamura, T., Higuchi, M., Kobayashi, T., Yoshita-Takahashi, M., Yamazaki, M., Abe, M., Sakimura, K., Kanda, Y., Kawamura, H., Jiang, S., Naito, M., Yoshizaki, T., Takahashi, M., Fujii, M. RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells. Europ. J. Immun. 45: 1512-1523, 2015. [PubMed: 25652366] [Full Text: https://doi.org/10.1002/eji.201444977]