Expressed in the yeast Saccharomyces cerevisiae, human ERK5 is a client of the Hsp90 chaperone that complements loss of the Slt2p (Mpk1p) cell integrity stress-activated protein kinase

Truman, Andrew W, Millson, Stefan H, Nuttall, James M, King, Victoria, Mollapour, Medhi, Prodromou, Chrisostomos, Pearl, Laurence H and Piper, Peter W (2006) Expressed in the yeast Saccharomyces cerevisiae, human ERK5 is a client of the Hsp90 chaperone that complements loss of the Slt2p (Mpk1p) cell integrity stress-activated protein kinase. Eukaryotic Cell, 5 (11). pp. 1914-1924. ISSN 1535-9778

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Abstract

ERK5 is a mitogen-activated protein (MAP) kinase regulated in human cells by diverse mitogens and stresses but also suspected of mediating the effects of a number of oncogenes. Its expression in the slt2Delta Saccharomyces cerevisiae mutant rescued several of the phenotypes caused by the lack of Slt2p (Mpk1p) cell integrity MAP kinase. ERK5 is able to provide this cell integrity MAP kinase function in yeast, as it is activated by the cell integrity signaling cascade that normally activates Slt2p and, in its active form, able to stimulate at least one key Slt2p target (Rlm1p, the major transcriptional regulator of cell wall genes). In vitro ERK5 kinase activity was abolished by Hsp90 inhibition. ERK5 activity in vivo was also lost in a strain that expresses a mutant Hsp90 chaperone. Therefore, human ERK5 expressed in yeast is an Hsp90 client, despite the widely held belief that the protein kinases of the MAP kinase class are non-Hsp90-dependent activities. Two-hybrid and protein binding studies revealed that strong association of Hsp90 with ERK5 requires the dual phosphorylation of the TEY motif in the MAP kinase activation loop. These phosphorylations, at positions adjacent to the Hsp90-binding surface recently identified for a number of protein kinases, may cause a localized rearrangement of this MAP kinase region that leads to creation of the Hsp90-binding surface. Complementation of the slt2Delta yeast defect by ERK5 expression establishes a new tool with which to screen for novel agonists and antagonists of ERK5 signaling as well as for isolating mutant forms of ERK5.

Item Type: Article
Keywords: Animals Gene Expression Regulation Genetic Complementation Test HSP90 Heat-Shock Proteins/antagonists & inhibitors/genetics/*metabolism Humans MADS Domain Proteins MAP Kinase Kinase 1/genetics/metabolism Mice Mitogen-Activated Protein Kinase 7/genetics/*metabolism Mitogen-Activated Protein Kinases/genetics/*metabolism Molecular Chaperones/genetics/*metabolism Mutation Phenotype Saccharomyces cerevisiae/cytology/genetics/*metabolism Saccharomyces cerevisiae Proteins/genetics/*metabolism Signal Transduction/physiology Transcription Factors/genetics/metabolism Transcription, Genetic Two-Hybrid System Techniques
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
Depositing User: Chrisostomos Prodromou
Date Deposited: 25 Feb 2015 10:29
Last Modified: 17 Mar 2017 03:58
URI: http://sro.sussex.ac.uk/id/eprint/44382

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