Qiu R G, Abo A, Steven Martin G
Department of Molecular and Cell Biology, University of California at Berkeley, 94720, USA.
Curr Biol. 2000 Jun 15;10(12):697-707. doi: 10.1016/s0960-9822(00)00535-2.
Rac and Cdc42 are members of the Rho family of small GTPases. They modulate cell growth and polarity, and contribute to oncogenic transformation by Ras. The molecular mechanisms underlying these functions remain elusive, however.
We have identified a novel effector of Rac and Cdc42, hPar-6, which is the human homolog of a cell-polarity determinant in Caenorhabditis elegans. hPar-6 contains a PDZ domain and a Cdc42/Rac interactive binding (CRIB) motif, and interacts with Rac1 and Cdc42 in a GTP-dependent manner. hPar-6 also binds directly to an atypical protein kinase C isoform, PKCzeta, and forms a stable ternary complex with Rac1 or Cdc42 and PKCzeta. This association results in stimulation of PKCzeta kinase activity. Moreover, hPar-6 potentiates cell transformation by Rac1/Cdc42 and its interaction with Rac1/Cdc42 is essential for this effect. Cell transformation by hPar-6 involves a PKCzeta-dependent pathway distinct from the pathway mediated by Raf.
These findings indicate that Rac/Cdc42 can regulate cell growth through Par-6 and PKCzeta, and suggest that deregulation of cell-polarity signaling can lead to cell transformation.
Rac和Cdc42是小GTP酶Rho家族的成员。它们调节细胞生长和极性，并参与Ras介导的致癌转化。然而，这些功能背后的分子机制仍不清楚。
我们鉴定出一种Rac和Cdc42的新型效应蛋白hPar-6，它是秀丽隐杆线虫中一种细胞极性决定因子的人类同源物。hPar-6含有一个PDZ结构域和一个Cdc42/Rac相互作用结合（CRIB）基序，并以GTP依赖的方式与Rac1和Cdc42相互作用。hPar-6还直接与一种非典型蛋白激酶C同工型PKCzeta结合，并与Rac1或Cdc42以及PKCzeta形成稳定的三元复合物。这种结合导致PKCzeta激酶活性的刺激。此外，hPar-6增强Rac1/Cdc42介导的细胞转化，并且它与Rac1/Cdc42的相互作用对于这种效应至关重要。hPar-6介导的细胞转化涉及一条不同于Raf介导途径的PKCzeta依赖途径。
这些发现表明Rac/Cdc42可以通过Par-6和PKCzeta调节细胞生长，并提示细胞极性信号传导失调可导致细胞转化。
