RPS6KA1
Description
The RPS6KA1 (ribosomal protein S6 kinase A1) is a protein-coding gene located on chromosome 1.
Ribosomal protein S6 kinase alpha-1 is an enzyme that in humans is encoded by the RPS6KA1 gene. This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 nonidentical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
RPS6KA1, also known as ribosomal protein S6 kinase alpha-1 (S6K-alpha-1), 90 kDa ribosomal protein S6 kinase 1, MAP kinase-activated protein kinase 1a, or ribosomal S6 kinase 1, is a serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling. It mediates mitogenic and stress-induced activation of transcription factors like CREB1, ETV1/ER81, and NR4A1/NUR77. RPS6KA1 regulates translation through phosphorylation of RPS6 and EIF4B and plays a crucial role in cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing the pro-apoptotic function of BAD and DAPK1. In fibroblasts, RPS6KA1 is required for EGF-stimulated phosphorylation of CREB1, leading to the transcriptional activation of several immediate-early genes. It phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP in response to mitogenic stimulation. Upon insulin signaling, RPS6KA1 indirectly regulates transcription by phosphorylating GSK3B at Ser-9 and inhibiting its activity. RPS6KA1 phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism, promoting translation initiation. It also phosphorylates EIF4B in response to insulin, enhancing its affinity for the EIF3 complex and stimulating cap-dependent translation. RPS6KA1 is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at Ser-1798, inhibiting its ability to suppress mTOR signaling. It mediates phosphorylation of RPTOR, regulating mTORC1 activity and potentially promoting rapamycin-sensitive signaling independently of the PI3K/AKT pathway. RPS6KA1 is also involved in the feedback regulation of mTORC1 and mTORC2 by phosphorylating DEPTOR. It mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1, suppressing their pro-apoptotic function. RPS6KA1 promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). It mediates induction of hepatocyte proliferation by TGFA through phosphorylation of CEBPB. RPS6KA1 is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, promoting its association with 14-3-3 proteins and preventing its translocation to the nucleus, thus inhibiting G1 progression. RPS6KA1 phosphorylates EPHA2 at Ser-897, and the RPS6KA-EPHA2 signaling pathway controls cell migration. In response to mTORC1 activation, RPS6KA1 phosphorylates EIF4B at Ser-406 and Ser-422, stimulating bicarbonate cotransporter SLC4A7 mRNA translation, increasing SLC4A7 protein abundance and function. In the context of microbial infection, RPS6KA1 promotes the late transcription and translation of viral lytic genes during Kaposi's sarcoma-associated herpesvirus/HHV-8 infection when constitutively activated.
RPS6KA1 is also known as HU-1, MAPKAPK1, MAPKAPK1A, RSK, RSK1, p90Rsk.
