Prenylcysteine analogs to study function of carboxylmethylation in signal transduction

Craig Volker, Michael H. Pillinger, Mark R. Philips, Jeffry B. Stock

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Carboxylmethylation of ras-related proteins is stimulated immediately on exposure of myeloid cells to inflammatory agonists. When the methylation reaction is inhibited with prenylcysteine analogs, G-protein-mediated signal transduction responses are disrupted, but responses to phorbol ester, calcium ionophore, and phospholipase C (PLC) remain intact. Furthermore, prenylcysteine analogs block GTPγS-induced aggregation of permeabilized platelets. Together, these results suggest that protein prenylcysteine methylation can play a role in signal transduction. A number of studies with AdoMet antagonists have suggested a role for methylation in cell-cycle regulation and stimulus-response coupling. Because the compounds generally inhibit all cellular methylation events, however, their effects have been difficult to interpret. On the other hand, prenylcysteine analogs have proved to be specific inhibitors of protein prenylcysteine methylation, as opposed to other types of methylation reactions. This enables the segregation of the role of methylation at C-terminal prenylcysteine residues from methylation at other sites, such as the carboxyl terminus of the catalytic subunit of PP2A. It should be emphasized, however, that prenl/lcysteine tails of proteins may interact with other target sites m addition to the methyltransferase enzyme(s), and prenylcysteine analogs may compete for these sites as well. One cannot assume that the inhibition of a response by the drugs necessarily implicates the involvement of a prenylcysteine methylation reaction. Studies with the analogs must be interpreted in conjunction with other results to ascertain the locus of their effects.

Original languageEnglish (US)
Pages (from-to)216-225
Number of pages10
JournalMethods in Enzymology
Volume250
Issue numberC
DOIs
StatePublished - Jan 1 1995

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

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