A human homolog of the C-elegans polarity determinant Par-6 links Rac and Cdc42 to PKC zeta signaling and cell transformation

Background: Rac and Cdc42 are members of the Rho family of small GTPases. T hey modulate cell growth and polarity, and contribute to oncogenic transfor mation by Ras. The molecular mechanisms underlying these functions remain e lusive, however. Results: We have identified a novel effector of Rac and Cdc42, hPar-6, whic h is the human homolog of a cell-polarity determinant in Caenorhabditis ele gans. hPar-6 contains a PDZ domain and a Cdc42/Rac interactive binding (CRI B) motif, and interacts with Rad and Cdc42 in a GTP-dependent manner. hPar- 6 also binds directly to an atypical protein kinase C isoform, PKC zeta, an d forms a stable ternary complex with Rac1 or Cdc42 and PKC zeta. This asso ciation results in stimulation of PKC zeta kinase activity. Moreover, hPar- 6 potentiates cell transformation by Rac1/Cdc42 and its interaction with Ra c1/Cdc42 is essential for this effect. Cell transformation by hPar-6 involv es a PKC zeta-dependent pathway distinct from the pathway mediated by Raf. Conclusions: These findings indicate that Rac/Cdc42 can regulate cell growt h through Par-6 and PKC zeta, and suggest that deregulation of cell-polarit y signaling can lead to cell transformation. (C) 2000 Elsevier Science Ltd. All rights reserved.