Ribosome S6 protein kinase (ribosomal56kinase, RSK) is an important member of cell signaling pathway. In 1985, irEkson and Xiler discovered a 90-cut protein kinase in Xenopus eggs, which can phosphorylate the 405 ribosomal subunit 56 protein, thereby promoting the translation of certain mRNAs and regulating cell growth and proliferation. Plays an important role in the process. This protein kinase is named RSK or 9Ps0rk. It was later discovered that the protein is a downstream substrate of mitogen-activated protein kinase. So far, four RSK subtypes have been found, which are widely expressed in higher eukaryotic cells. With the gradual progress of research, people have discovered that RSK plays an important role in various life activities, including regulating gene transcription, participating in cell cycle regulation, promoting cell proliferation and differentiation, regulating cell survival and apoptosis, and participating in the formation of learning and memory, etc.
Classifications
The RSK family is a special class of serine / threonine protein kinases. So far, four RSK subtypes have been found: RSK-1, RSK-2, RSK-3, and RSK-4; RS4K only exists in human tissues and organs, and the other three subtypes are found in a variety of organisms. Extensive expression. Koiln, M. reported that in the middle stage of mouse embryonic development, the expression of RSKZ first increased at the somite site, followed by the sensory center of the cranial nerve and the dorsal root ganglia of the spinal nerve. RSKZ is always expressed at a high level during the development of the nervous system, and is closely related to the expression of IP3-dependent protein kinase I. However, after birth of mice 2, the expression of RSKZ and PDKI in the hippocampal pyramidal cell layer and cerebral cortex appeared to be separated, that is, the level of PDKI expression remained unchanged, while the expression of RSKZ was significantly reduced. Later, people successively discovered 7P0RsK, mitogen stress-activated protein kinase (mitogenstressactivaetd). Proetiniknase (MSK) and RsK-B. Their structure is similar to RSK in some aspects, but there are obvious differences in coding genes and functions.
Structure of SRK
The four subtypes of RSK have the same basic structure, with two kinase domains (NTK and CTK) and a linker region. eTK is a calcium ion-calmodulin-dependent kinase that can activate NTK after phosphorylation by upstream kinases, while NTK belongs to AGC kinase, which can act on the substrate of RSK to phosphorylate and recognize basic polypeptide sequences. The activation of the phosphorylation site of the linker can also regulate NTK activity. In addition, the C-terminal tail contains a specific ERK (xE is better than ellularisgnalergula and iknase) binding site, which binds EKR to put RSK further under the regulation of ERK. Six serine/threonine phosphorylation sites have been discovered. Ser221 site in Nl, K active region (activated by PDKI); Thr573 (ERK activation site) on CTK; Thr359/Ser363 (ERK activation site) on Linker and eSr380 autophosphorylation site (Cl K activation site).
RSK activity regulation
Although RSK is the earliest discovered ERK substrate, its activation mechanism is still not clear. Its two unique kinase domains and numerous phosphorylation sites make it difficult to study the activation mechanism of RSK. Studies have shown that ERK can phosphorylate and activate CTK, and activated CTK can phosphorylate NTK, thereby promoting RSK autophosphorylation and activation. The phosphorylation of serine in the NTK active region is essential for RSK activity. In vitro experiments, mutation of this site to alanine can block phosphorylation of substrates by all subtypes of RSK. When CTK or NTK were inactivated, the phosphorylation level of Ser221 site in RSKI was significantly reduced. However, many studies have shown that RSK activity is also regulated by PDKI. PDKI is widely distributed, has high activity in cells, and is not regulated by extracellular signals. Epidermal growth factor EGF can activate RSK; when PDKI expression is abnormal, the activation level of RSKZ and RSK3 by EGF can only reach 70% of the maximum level, while RSKI only has a maximum level of 40%. The mutation of Ser227Glu in RSKZ can block the activation of RSKZ by PDKI, indicating that PDKI participates in the activation of RSKZ by phosphorylating Ser227. It can be seen that the activation of RSK is regulated by three protein kinases, ERK, CTK and PDKI. These three interact or cooperate with each other to participate in the regulation of RSK activity. In addition to being inactivated by phosphatase dephosphorylation, RSK can also reduce its activity through negative feedback regulation. It has been reported that under EGF stimulation, RSK phosphorylates 505 serine / threonine residues, and the latter phosphorylation can negatively inhibit Ras activity, thereby reducing RSK activity through the Ras-ERK pathway.
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