Abstract
RSKB, a 90-kDa ribosomal S6 protein kinase family (RSK) member with two complete catalytic domains connected by a linker, is activated through p38- and ERK-mitogen-activated protein kinases. The N-terminal kinases of RSKs phosphorylate substrates; activation requires phosphorylation of linker and C-terminal kinase sites. Unlike other RSKs, the activation loop phosphorylation sites of both catalytic domains of RSKB, Ser(196) and Thr(568), were required for activity. RSKB activation depended on phosphorylation of linker Ser(343) and Ser(360) and associated with phosphorylation of nonconserved Ser(347), but Ser(347)-deficient RSKB retained partial activity. The known protein kinase A and protein kinase C inhibitors, H89 and Ro31-8220, blocked RSKB activity. Treatment of HeLa cells with tumor necrosis factor, epidermal growth factor, phorbol 12-myristate 13-acetate, and ionomycin but not with insulin resulted in strong activation of endogenous RSKB. High RSKB activity and Ser(347)/Ser(360) phosphorylation persisted for 3 h in tumor necrosis factor-treated cells, in contrast to the short bursts of p38, ERK, and RSK1-3 activities. In conclusion, a variety of stimuli induced phosphorylation and activation of RSKB through both p38 and ERK pathways; the persistence of activation indicated that RSKB selectively escaped cell mechanisms causing rapid deactivation of upstream p38 and ERK and other RSKs.
Highlights
RSKB, a 90-kDa ribosomal S6 protein kinase family (RSK) member with two complete catalytic domains connected by a linker, is activated through p38- and ERK-mitogen-activated protein kinases
It is noted that the RSK2 mutant S227E-RSK2 [51], which is homologous to inactive S196E-RSKB, displayed strong activation by EGF treatment in COS7 cell transfectants, showing that here the Glu mutation in the NTD was permissive for activation of the whole enzyme
These divergent properties of RSK1, RSK2, and RSKB, which are explained by structural differences and experimental conditions, point to distinct control mechanisms among RSKs through distinct upstream kinases such as PDK1 in addition to mitogen-activated protein kinase (MAPK) [51]
Summary
Tor [55], are phosphorylated by the NTD, whereas the linker and CTD have a role in NTD activation (49 –51, 56). Two novel members of the RSK family were discovered, MSK1 and RSKB [61, 63, 64], which in contrast to RSK1–3 were under dominant p38 control and responded, albeit more weakly, to activation of the ERK pathway. Both MSK1 and RSKB appeared to phosphorylate CREB, indicating a symmetric downstream effector of ERK and p38 pathways [42, 61, 63]. RSKB in cells stimulated by TNF treatment was activated within 10 min, and its activation persisted for prolonged periods, in contrast to the burst and rapid return to basal activity levels of the upstream MAPKs, p38 and ERK, and of the parallel RSK1–3, indicating that RSKB selectively escaped from a more common down-regulatory control of MAPKs and other RSKs
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