RPS6KA3 : ribosomal protein S6 kinase A3

Description

The RPS6KA3 (ribosomal protein S6 kinase A3) is a protein-coding gene located on chromosome X.

The RPS6KA3 gene provides instructions for making a protein that is part of a family called ribosomal S6 kinases (RSKs). These proteins help regulate the activity of certain genes and are involved in signaling within cells. RSK proteins are thought to play a role in several important cellular processes including cell growth and division (proliferation), cell specialization (differentiation), and the self-destruction of cells (apoptosis). The protein made by the RPS6KA3 gene appears to play an important role in the brain. The protein is involved in cell signaling pathways that are required for learning, the formation of long-term memories, and the survival of nerve cells.

RPS6KA3 encodes a serine/threonine-protein kinase that functions downstream of ERK signaling, mediating mitogenic and stress-induced activation of transcription factors like CREB1, ETV1/ER81, and NR4A1/NUR77. It regulates translation through RPS6 and EIF4B phosphorylation, contributing to cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing the pro-apoptotic activity of BAD and DAPK1. In fibroblasts, RPS6KA3 is crucial for EGF-stimulated phosphorylation of CREB1 and histone H3, leading to the transcriptional activation of immediate-early genes. In response to mitogenic stimuli, it phosphorylates and activates NR4A1/NUR77, ETV1/ER81, and the cofactor CREBBP. Upon insulin signaling, it indirectly regulates gene transcription by phosphorylating and inhibiting GSK3B. RPS6KA3 phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism, promoting translation initiation. It phosphorylates EIF4B in response to insulin, enhancing its affinity for the EIF3 complex and stimulating cap-dependent translation. RPS6KA3 participates in the mTOR nutrient-sensing pathway by phosphorylating TSC2, inhibiting its suppression of mTOR signaling, and by phosphorylating RPTOR, regulating mTORC1 activity. It promotes cell survival by phosphorylating and suppressing the pro-apoptotic proteins BAD and DAPK1. RPS6KA3 is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, promoting its association with 14-3-3 proteins and preventing nuclear translocation, thereby facilitating G1 progression. In LPS-stimulated dendritic cells, it participates in TLR4-induced macropinocytosis. In myeloma cells, it acts as an effector of FGFR3-mediated transformation signaling, following phosphorylation by FGFR3. RPS6KA3 negatively regulates EGF-induced MAPK1/3 phosphorylation by phosphorylating SOS1, creating binding sites for YWHAB and YWHAE, which contribute to the negative regulation of MAPK1/3 phosphorylation. It phosphorylates EPHA2, regulating cell migration. RPS6KA3 acts as a regulator of osteoblast differentiation by phosphorylating and promoting ATF4 transactivation activity. In quiescent cells, RPS6KA3 forms a complex with either MAPK1/ERK2 or MAPK3/ERK1, transiently dissociating upon mitogenic stimulation. It interacts with NFATC4, ETV1/ER81, and FGFR1.

RPS6KA3 is also known as CLS, HU-3, ISPK-1, MAPKAPK1B, MRX19, RSK, RSK2, S6K-alpha3, XLID19, p90-RSK2, pp90RSK2.

Associated Diseases

• Coffin-Lowry syndrome
• Symptomatic form of Coffin-Lowry syndrome in female carriers
• Mental retardation, X-linked 19