Characterization of Regulatory Events Associated with Membrane Targeting of p90 Ribosomal S6 Kinase 1

doi:10.1128/MCB.21.21.7470-7480.2001

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Molecular and Cellular Biology, November 2001, p. 7470-7480, Vol. 21, No. 21
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.21.7470-7480.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Characterization of Regulatory Events Associated with Membrane Targeting of p90 Ribosomal S6 Kinase 1

Stephanie A. Richards, Valley C. Dreisbach, Leon O. Murphy, and John Blenis^*

Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

Received 30 August 2001/Returned for modification 11 October 2000/Accepted 27 July 2001

RSK is a serine/threonine kinase containing two distinct catalytic domains. Found at the terminus of the Ras/extracellularsignal-regulated kinase (ERK)-mitogen-activated protein kinase(MAPK) kinase cascade, mitogen-stimulated ribosomal S6 kinase(RSK) activity requires multiple inputs. These inputs includephosphorylation of the C-terminal kinase domain activation loopby ERK1/2 and phosphorylation of the N-terminal kinase domainactivation loop by phosphoinositide-dependent protein kinase-1(PDK1). Previous work has shown that upon mitogen stimulation,RSK accumulates in the nucleus. Here we show that prior to nucleartranslocation, epidermal growth factor-stimulated RSK1 transientlyassociates with the plasma membrane. Myristylation of wild-typeRSK1 results in an activated enzyme in the absence of added growthfactors. When RSK is truncated at the C terminus, the characterizedERK docking is removed and RSK phosphotransferase activity iscompletely abolished. When myristylated, however, this myristylatedC-terminal truncated form (myrCTT) is activated at a level equivalentto myristylated wild-type (myrWT) RSK. Both myrWT RSK and myrCTTRSK can signal to the RSK substrate c-Fos in the absence of mitogenactivation. Unlike myrWT RSK, myrCTT RSK is not further activatedby serum. Only the myristylated RSK proteins are basally phosphorylatedon avian RSK1 serine 381, a site critical for RSK activity. Themyristylated and unmyristylated RSK constructs interact with PDK1upon mitogen stimulation, and this interaction is insensitiveto the MEK inhibitor UO126. Because a kinase-inactive CTT RSKcan be constitutively activated by targeting to the membrane,we propose that ERK may have a dual role in early RSK activationevents: preliminary phosphorylation of RSK and escorting RSK toa membrane-associated complex, where additional MEK/ERK-independentactivating inputs areencountered.

^* Corresponding author. Mailing address: Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115.Phone: (617) 432-4848. Fax: (617) 432-1144. E-mail: jblenis{at}hms.harvard.edu.

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