Interaction of farnesylated PRL-2, a protein-tyrosine phosphatase, with the beta-subunit of geranylgeranyltransferase II

Protein of regenerating liver (PRL)-1, -2, and -3 comprise a subgroup of cl osely related protein-tyrosine phosphatases featuring a C-terminal prenylat ion motif conforming to either the consensus sequence for farnesylation, CA AX, or geranylgeranylation, CCXX. Yeast two-hybrid screening for PRL-2-inte racting proteins identified the beta -subunit of Rab geranylgeranyltransfer ase II (beta GGT II). The specific interaction of beta GGT II with PRL-2 bu t not with PRL-1 or -3 occurred in yeast and HeLa cells. Chimeric PRL-1/-2 molecules were tested for their interaction with beta GGT II, and revealed that the C-terminal region of PRL-2 is required for interaction, possibly t he PRL variable region immediately preceeding the CAAX box. Additionally, P RL-2 prenylation is prequisite for beta GGT II binding. As prenylated PRL-2 is localized to the early endosome, we propose that this is where the inte raction occurs. PRL-2 is not a substrate for beta GGT II, as isoprenoid ana lysis showed that PRL-2 was solely farnesylated in vivo. Co-expression of t he a-subunit (a) of GGT II, beta GGT II, and PRL-2 resulted in alpha/beta G GT II heterodimer formation and prevented PRL-2 binding. Expression of PRL- 2 alone inhibited the endogenous alpha/beta GGT II activity in HeLa cells. Together, these results indicate that the binding of alpha GGT II and PRL-2 to beta GGT II is mutually exclusive, and suggest that PRL-2 may function as a regulator of GGT II activity.