The molecular chaperone Hsp90 is required for signal transduction by wild-type Hck and maintenance of its constitutively active counterpart

We have investigated the relationship between the molecular chaperone heat shock protein-90 (Hsp90) and the signal transducing capacity of the Src-fam ily kinase Hck. Inhibition of Hsp90 with geldanamycin suppressed the abilit y of bacterial lipopolysaccharide to enhance the cell adhesion properties o f macrophages, a phenomenon most likely explained by the reduced expression and activity of Hck in macrophages lacking Hsp90 function. The contributio n of Hsp90 to signal transduction by Hck was biochemically dissected furthe r by examining its role in the de novo folding and maintenance of wild-type Hck and its constitutively active counterpart, Hck499F. The folding of nas cent wild-type Hck and Hck499F into catalytically active conformations, and their accumulation in cells was found to be dependent on Hsp90 function. N otably, mature Hck499F had a greater requirement for on-going support from Hsp90 than did mature wild-type Hck. This particular finding might have imp ortant implications for our understanding of the evolution of oncogenic pro tein kinases.