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J. Biol. Chem., Vol. 276, Issue 8, 5892-5899, February 23, 2001

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C-terminal Elements Control Location, Activation Threshold, and p38 Docking of Ribosomal S6 Kinase B (RSKB)^*

Mar Tomás-Zuber^§, Jean-Luc Mary^¶§, François Lamour, Daniel Bur, and Werner Lesslauer^**§§

From the Departments of  Central Nervous System Diseases, ^¶ Vascular and Metabolic Diseases, and  Discovery Chemistry of F. Hoffmann-LaRoche, Ltd., CH-4070 Basel, Switzerland and the Departments of ^** Epidemiology and Public Health and  Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-0834

RSKB, a p90 ribosomal S6 protein kinase with two catalytic domains, is activated by p38- and extracellular signal-regulated kinase mitogen-activated protein kinase pathways. The sequences between the two catalytic domains and of the C-terminal extension contain elements that control RSKB activity. The C-terminal extension of RSKB presents a putative bipartite ⁷¹³KRX₁₄KRRKQKLRS⁷³⁷ nuclear location signal. The distinct cytoplasmic and nuclear locations of various C-terminal truncation mutants supported the hypothesis that the nuclear location signal was essential to direct RSKB to the nuclear compartment. The ⁷²⁵APLAKRRKQKLRS⁷³⁷ sequence also was essential for the intermolecular association of RSKB with p38. The activation of RSKB through p38 could be dissociated from p38 docking, because RSKB truncated at Ser⁶⁸¹ strongly responded to p38 pathway activity. Interestingly, ^725-772-RSKB was nearly nonresponsive to p38. Sequence alignment with the autoinhibitory C-terminal extension of Ca⁺²/calmodulin-dependent protein kinase I predicted a conserved regulatory ⁷⁰⁸AFN⁷¹⁰ motif. Alanine mutation of the key Phe⁷⁰⁹ residue resulted in strongly elevated basal level RSKB activity. A regulatory role also was assigned to Thr⁶⁸⁷, which is located in a mitogen-activated protein kinase phosphorylation consensus site. These findings support that the RSKB C-terminal extension contains elements that control activation threshold, subcellular location, and p38 docking.

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