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Sci. STKE, 21 January 2003
Vol. 2003, Issue 166, p. tw32
[DOI: 10.1126/stke.2003.166.tw32]

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MAPK Signaling Auto-Ubiquitylation Inhibits Kinase Activity

The mitogen-activated protein kinase (MAPK) kinase kinase 1 (MEKK1) stimulates the extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) pathways. MEKK1 has a functional ubiquitin ligase E3 domain of the type called plant homeobox domain (PHD) that can ubiquitylate ERK2 (see related resources). Witowsky and Johnson show that MEKK1 is also able to ubiquitylate itself and that this inhibits its kinase activity toward the MAPKKs MKK1 and MKK4 in vitro. MEKK1 ubiquitylating activity required the kinase activity of MEKK1. In transfected cells, expression of MEKK1 stimulated the ERK and JNK pathways, but coexpression with ubiquitin inhibited this response. Activation of the ERK and JNK pathways was restored in the presence of ubiquitin if a mutant form of MEKK1 lacking a critical residue in the PHD was used. Ubiquitylated MEKK1 was not targeted for degradation by the proteasome, but ubiquitin appeared to serve a regulatory function for the kinase activity. Thus, autoubiquiylation of MEKK1 may serve to control the extent of activation of the downstream pathways and represents yet another example of ubiquitin serving as a regulator of activity without signaling protein destruction.

J. A. Witowsky, G. L. Johnson, Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways. J. Biol. Chem. 278, 1403-1406 (2003). [Abstract] [Full Text]

Citation: Auto-Ubiquitylation Inhibits Kinase Activity. Sci. STKE 2003, tw32 (2003).



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