Interaction of protein kinase C ζ with ZIP, a novel protein kinase C-binding protein

The atypical protein kinase C (PKC) member PKC-ζ has been implicated in several signal transduction pathways regulating differentiation, proliferation or apoptosis of mammalian cells. We report here the identification of a cytoplasmic and membrane-associated protein that we name zeta-interacting protein (ZIP) and that interacts with the regulatory domain of PKC-ζ but not classic PKCs. The structural motifs in ZIP include a recently defined ZZ zinc finger as a potential protein binding module, two PEST sequences and a novel putative protein binding motif with the consensus sequence YXDEDX(5)SDEE/D. ZIP binds to the pseudosubstrate region in the regulatory domain of PKC-ζ and is phosphorylated by PKC-ζ in vitro. ZIP dimerizes via the same region that promotes binding to PKC-ζ suggesting a competitive situation between ZIP:ZIP and ZIP:PKC-ζ complexes. In the absence of PKC-ζ proper subcellular localization of ZIP is impaired and we show that intracellular targeting of ZIP is dependent on a balanced interaction with PKC-ζ. Taking into account the recent isolation of ZIP by others in different contexts we propose that ZIP may function as a scaffold protein linking PKC-ζ to protein tyrosine kinases and cytokine receptors.