Interaction of Farnesylated PRL-2, a Protein-tyrosine Phosphatase, with the β-Subunit of Geranylgeranyltransferase II

Protein of regenerating liver (PRL)-1, -2, and -3 comprise a subgroup of closely related protein-tyrosine phosphatases featuring a C-terminal prenylation motif conforming to either the consensus sequence for farnesylation, CAAX, or geranylgeranylation, CCXX. Yeast two-hybrid screening for PRL-2-interacting proteins identified the β-subunit of Rab geranylgeranyltransferase II (βGGT II). The specific interaction of βGGT II with PRL-2 but not with PRL-1 or -3 occurred in yeast and HeLa cells. Chimeric PRL-1/-2 molecules were tested for their interaction with βGGT II, and revealed that the C-terminal region of PRL-2 is required for interaction, possibly the PRL variable region immediately preceeding the CAAX box. Additionally, PRL-2 prenylation is prequisite for βGGT II binding. As prenylated PRL-2 is localized to the early endosome, we propose that this is where the interaction occurs. PRL-2 is not a substrate for βGGT II, as isoprenoid analysis showed that PRL-2 was solely farnesylated in vivo. Co-expression of the α-subunit (α) of GGT II, βGGT II, and PRL-2 resulted in α/βGGT II heterodimer formation and prevented PRL-2 binding. Expression of PRL-2 alone inhibited the endogenous α/βGGT II activity in HeLa cells. Together, these results indicate that the binding of αGGT II and PRL-2 to βGGT II is mutually exclusive, and suggest that PRL-2 may function as a regulator of GGT II activity.