AMINO-TERMINAL PALMITATE OR POLYBASIC DOMAIN CAN PROVIDE REQUIRED 2ND SIGNAL TO MYRISTATE FOR MEMBRANE-BINDING OF P56(LCK)

Recent work has shown that several members of the src family of protein tyrosine kinases (PTKs) are modified by palmitoylation, including p56(lck) and p59(fyn) but not p60(src). Mapping of the sites of palmitoylation in p56(lck) identified cys(3) as the major site and cys(5) as a minor site of palmitoylation. A non-palmitoylated p56(lck)(cys(3,5)-->ser) mutant was localized exclusively in the cytoplasm despite the presence of amino-terminal myristoylation, thus indicating that palmitoylation of p56(lck) was necessary for membrane binding. The addition of a domain of six lysine residues to a non-palmitoylated p56(lck) mutant was sufficient to re-establish membrane binding but not to target the non-palmitoylated p56(lck) to caveolae. These results establish that two signals, myristoylation plus either palmitoylation or a polybasic domain, are necessary for membrane binding of are family PTKs. (C) 1995 Academic Press, Inc.