title: The molecular chaperone Hsp90 is required for signal transduction by wild-type Hck and maintenance of its constitutively active counterpart.
abstract: We have investigated the relationship between the molecular chaperone heat shock protein-90 (Hsp90) and the signal transducing capacity of the Src-family kinase Hck. Inhibition of Hsp90 with geldanamycin suppressed the ability of bacterial lipopolysaccharide to enhance the cell adhesion properties of macrophages, a phenomenon most likely explained by the reduced expression and activity of Hck in macrophages lacking Hsp90 function. The contribution of Hsp90 to signal transduction by Hck was biochemically dissected further by examining its role in the de novo folding and maintenance of wild-type Hck and its constitutively active counterpart, Hck499F. The folding of nascent wild-type Hck and Hck499F into catalytically active conformations, and their accumulation in cells was found to be dependent on Hsp90 function. Notably, mature Hck499F had a greater requirement for on-going support from Hsp90 than did mature wild-type Hck. This particular finding might have important implications for our understanding of the evolution of oncogenic protein kinases.
authors.affiliation: Molecular Biology Laboratory, Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria 3050, Australia. Glen.Scholz@ludwig.edu.au
authors.forename: G M
authors.initials: GM
authors.lastname: Scholz
authors.forename: S D
authors.initials: SD
authors.lastname: Hartson
authors.forename: K
authors.initials: K
authors.lastname: Cartledge
authors.forename: L
authors.initials: L
authors.lastname: Volk
authors.forename: R L
authors.initials: RL
authors.lastname: Matts
authors.forename: A R
authors.initials: AR
authors.lastname: Dunn
mesh_terms: D000818:Animals; D016227:Benzoquinones; D020134:Catalytic Domain / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D047029:Lactams, Macrocyclic; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D050722:Oncogene Protein v-cbl; D010766:Phosphorylation / Q000187:drug effects; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck; D011809:Quinones / Q000494:pharmacology; D015682:Retroviridae Proteins, Oncogenic / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000187:drug effects / Q000378:metabolism; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D050722:Oncogene Protein v-cbl; D011518:Proto-Oncogene Proteins; D011809:Quinones; D015682:Retroviridae Proteins, Oncogenic; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C001277:geldanamycin