TAXOL SHARES THE ABILITY OF BACTERIAL LIPOPOLYSACCHARIDE TO INDUCE TYROSINE PHOSPHORYLATION OF MICROTUBULE-ASSOCIATED PROTEIN-KINASE

Microtubule-associated proteins may mediate the activation of macropha ges by bacterial LPS. Three lines of evidence support this hypothesis: a) Taxol, a microtubule-binding diterpene, mimics the ability of LPS to induce cytokines and down-regulate receptors for TNF-alpha. In reco mbinant inbred mouse strains differing at the Lps gene, responsiveness to these effects of Taxol co-segregates with responsiveness to LPS. b ) In vitro, LPS binds specifically to MT and preferentially to beta-tu bulin. c) LPS activates microtubule-associated protein-2 kinase (MAPK) . The present studies bring together and extend these lines of evidenc e. a) Taxol, like LPS, rapidly induces tyrosine phosphorylation of MAP K in mouse macrophages, and triggers MAPK to phosphorylate an exogenou s substrate. b) Tyrosine phosphorylation of MAPK is an extremely rapid cellular response both to taxol and LPS. c) Macrophages from C3H/HeJ mice, which carry a defective Lps gene, fail to activate MAPK in respo nse to taxol or LPS, although they activate MAPK in response to insuli n or IFN-gamma. These results suggest that tyrosine phosphorylation of MAPK is among the earliest known response of macrophages to LPS. Taxo l mimics LPS with respect to immediate MAPK activation, later transcri ptional events, and the genetic control of both sets of responses. LPS and taxol thus appear to share a nearly step in a functionally import ant signal transduction pathway that may involve MT.