ERK1/2/5 activate RSK1/2/3

The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK.<br>RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398.<br>Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2. <br>

90百分位数核糖体S6激酶（RSK1-4）构成一类位于ERK途径末端的丝氨酸/苏氨酸激酶家族。RSK家族成员在丝氨酸/苏氨酸激酶中显得尤为特殊，它们含有两个不同的激酶结构域，且这两个结构域均具有催化活性。C端激酶结构域被认为参与自磷酸化，这是RSK激活的关键步骤，而N端激酶结构域，与AGC超家族激酶成员同源，负责所有已知外源性RSK底物的磷酸化。RSKs可被细胞质中的ERKs（ERK1、2、5）以及细胞核中的ERKs激活，它们既有细胞质底物，也有细胞核底物，并且能够从细胞核移动到细胞质。ERKs通过位于RSKC端附近的对接位点与RSK相互作用，以高效激活RSK。RSK激活的研究主要集中于ERK1和ERK2。RSK激活会导致四个关键残基Ser239、Ser381、Ser398和Thr590以及两个额外位点Thr377和Ser749的磷酸化（氨基酸编号指代RSK1）。ERK在RSK1激活中至少扮演两个角色：首先，激活的ERK在Thr590处磷酸化RSK1，可能还在Thr377和Ser381处磷酸化；其次，ERK将RSK1带到与膜结合激酶邻近的位置，这些激酶可能磷酸化RSK1在Ser381和Ser398处的残基。此外，RSKs与ERK1/2形成的一种复合体，在生长因子信号传导过程中会暂时解离。复合体的解离需要RSK1丝氨酸749的磷酸化，这是一个位于ERK对接位点附近，受生长因子调控的磷酸化位点。丝氨酸749由RSK1自身的N端激酶结构域磷酸化。ERK1/2对接到RSK2和RSK3的过程也以类似方式进行调控。生长因子刺激后RSK激活的持续时间取决于RSK/ERK复合体的持续时间，而这一持续时间在不同RSK同种异构体之间有所不同。RSK1和RSK2在生长因子刺激后容易从ERK1/2解离，但RSK3与活性ERK1/2的关联时间更长，且其活性维持时间也长于RSK1和RSK2。