Rac1-induced cell migration requires membrane recruitment of the nuclear oncogene SET.
The Rho GTPase Rac1 controls cell adhesion and motility. The effector loop of Rac1 mediates interactions with downstream effectors, whereas its C-terminus binds the exchange factor beta-Pix, which mediates Rac1 targeting and activation. Here, we report that Rac1, through its C-terminus, also binds the nuclear oncogene SET/I2PP2A, an inhibitor of the serine/threonine phosphatase PP2A. We found that SET translocates to the plasma membrane in cells that express active Rac1 as well as in migrating cells. Membrane targeting of SET stimulates cell migration in a Rac1-dependent manner. Conversely, reduction of SET expression inhibits Rac1-induced migration, indicating that efficient Rac1 signalling requires membrane recruitment of SET. The recruitment of the SET oncogene to the plasma membrane represents a new feature of Rac1 signalling. Our results suggest a model in which Rac1-stimulated cell motility requires both effector loop-based downstream signalling and recruitment of a signalling amplifier, that is, SET, through the hypervariable C-terminus.
ten Klooster
Jean Paul
JP
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan, Amsterdam, The Netherlands.
Leeuwen
Ingrid v
Iv
Scheres
Nina
N
Anthony
Eloise C
EC
Hordijk
Peter L
PL
D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism* / Q000502:physiology; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D056488:Histone Chaperones; D006801:Humans; D008954:Models, Biological; D009707:Nucleosomes / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D009707:Nucleosomes; C107953:RAC1 protein, human; C513473:SET protein, human; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein