The GIT-associated kinase PAK targets to the centrosome and regulates Aurora-A.
Previously, we showed PAK-PIX-GIT targets and regulates focal adhesions; here, we uncover a different function for the complex at the centrosome. Active PAK1 is particularly evident in mitosis and phosphorylates the centrosomal adaptor GIT1 on serine 517. Interestingly, direct centrosome targeting activates the kinase via a process not requiring Rho GTPases; excision of the centrosome prevents this activation. Once activated, PAK1 dissociates from PIX/GIT but can bind to and phosphorylate the important centrosomal kinase Aurora-A. PAK1 promotes phosphorylation of Aurora-A on Thr288 and Ser342, which are key sites for kinase activation in mitosis. In vivo PAK activation causes an accumulation of activated Aurora-A; conversely, when betaPIX is depleted or PAK is inhibited, there is a delay in centrosome maturation. These observations may underlie reported effects of active PAK on cells, including histone H3 phosphorylation, alterations in centrosome number, and progression through mitosis.
Zhao
Zhuo-Shen
ZS
GSK-IMCB Group, Institute of Molecular and Cell Biology, Proteos Building, 61 Biopolis Drive, Singapore 138673.
Lim
Jet Phey
JP
Ng
Yuen-Wai
YW
Lim
Louis
L
Manser
Ed
E
D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism*; D002522:Chlorocebus aethiops; D020690:GTPase-Activating Proteins; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008938:Mitosis; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D054462:p21-Activated Kinases
D018797:Cell Cycle Proteins; D020690:GTPase-Activating Proteins; C120766:Git1 protein, mouse; D006657:Histones; D010750:Phosphoproteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C576918:Aurka protein, mouse; C576920:Aurka protein, rat; D064096:Aurora Kinase A; D064127:Aurora Kinases; C515903:PAK1 protein, human; C515907:PAK2 protein, human; C515905:Pak1 protein, mouse; C515906:Pak1 protein, rat; C515909:Pak2 protein, mouse; C515910:Pak2 protein, rat; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases