Obermeier A, Ahmed S, Manser E, Yen S C, Hall C, Lim L
Glaxo-IMCB Group, Institute of Molecular and Cell Biology, Singapore.
EMBO J. 1998 Aug 3;17(15):4328-39. doi: 10.1093/emboj/17.15.4328.
The serine/threonine kinase p21-activated kinase (PAK) has been implicated as a downstream effector of the small GTPases Rac and Cdc42. While these GTPases evidently induce a variety of morphological changes, the role(s) of PAK remains elusive. Here we report that overexpression of betaPAK in PC12 cells induces a Rac phenotype, including cell spreading/membrane ruffling, and increased lamellipodia formation at growth cones and shafts of nerve growth factor-induced neurites. These effects are still observed in cells expressing kinase-negative or Rac/Cdc42 binding-deficient PAK mutants, indicating that kinase- and p21-binding domains are not involved. Furthermore, lamellipodia formation in all cell lines, including those expressing Rac binding-deficient PAK, is inhibited significantly by dominant-negative RacN17. Equal inhibition is achieved by blocking PAK interaction with the guanine nucleotide exchange factor PIX using a specific N-terminal PAK fragment. We conclude that PAK, via its N-terminal non-catalytic domain, acts upstream of Rac mediating lamellipodia formation through interaction with PIX.
丝氨酸/苏氨酸激酶p21活化激酶（PAK）被认为是小GTP酶Rac和Cdc42的下游效应器。虽然这些GTP酶明显诱导多种形态变化，但PAK的作用仍不清楚。在此我们报告，在PC12细胞中βPAK的过表达诱导Rac表型，包括细胞铺展/膜皱襞，以及在神经生长因子诱导的神经突的生长锥和轴上增加板状伪足的形成。在表达激酶阴性或Rac/Cdc42结合缺陷型PAK突变体的细胞中仍观察到这些效应，表明激酶和p21结合结构域不参与其中。此外，在所有细胞系中，包括那些表达Rac结合缺陷型PAK的细胞系，板状伪足的形成被显性负性RacN17显著抑制。通过使用特定的N端PAK片段阻断PAK与鸟嘌呤核苷酸交换因子PIX的相互作用可实现同等程度的抑制。我们得出结论，PAK通过其N端非催化结构域，在Rac上游起作用，通过与PIX相互作用介导板状伪足的形成。
