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

2001; Taylor & Francis; Volume: 21; Issue: 21 Linguagem: Inglês

10.1128/mcb.21.21.7470-7480.2001

1098-5549

Stephanie Richards, Valley Dreisbach, Leon O. Murphy, John Blenis,

PI3K/AKT/mTOR signaling in cancer

RSK is a serine/threonine kinase containing two distinct catalytic domains.Found at the terminus of the Ras/extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) kinase cascade, mitogen-stimulated ribosomal S6 kinase (RSK) activity requires multiple inputs.These inputs include phosphorylation of the C-terminal kinase domain activation loop by ERK1/2 and phosphorylation of the N-terminal kinase domain activation 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 nuclear translocation, epidermal growth factor-stimulated RSK1 transiently associates with the plasma membrane.Myristylation of wild-type RSK1 results in an activated enzyme in the absence of added growth factors.When RSK is truncated at the C terminus, the characterized ERK docking is removed and RSK phosphotransferase activity is completely abolished.When myristylated, however, this myristylated C-terminal truncated form (myrCTT) is activated at a level equivalent to myristylated wild-type (myrWT) RSK.Both myrWT RSK and myrCTT RSK can signal to the RSK substrate c-Fos in the absence of mitogen activation.Unlike myrWT RSK, myrCTT RSK is not further activated by serum.Only the myristylated RSK proteins are basally phosphorylated on avian RSK1 serine 381, a site critical for RSK activity.The myristylated and unmyristylated RSK constructs interact with PDK1 upon mitogen stimulation, and this interaction is insensitive to the MEK inhibitor UO126.Because a kinase-inactive CTT RSK can be constitutively activated by targeting to the membrane, we propose that ERK may have a dual role in early RSK activation events: preliminary phosphorylation of RSK and escorting RSK to a membrane-associated complex, where additional MEK/ERK-independent activating inputs are encountered.