Rac1 and a GTPase-activating protein, MgcRacGAP, are required for nuclear translocation of STAT transcription factors

Abstract

STAT transcription factors are tyrosine phosphorylated upon cytokine stimulation and enter the nucleus to activate target genes. We show that Rac1 and a GTPase-activating protein, MgcRacGAP, bind directly to p-STAT5A and are required to promote its nuclear translocation. Using permeabilized cells, we find that nuclear translocation of purified p-STAT5A is dependent on the addition of GTP-bound Rac1, MgcRacGAP, importin α, and importin β. p-STAT3 also enters the nucleus via this transport machinery, and mutant STATs lacking the MgcRacGAP binding site do not enter the nucleus even after phosphorylation. We conclude that GTP-bound Rac1 and MgcRacGAP function as a nuclear transport chaperone for activated STATs.

Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration

“…In contrast, some studies suggest that RacGAP1 is able to mediate some of its functions independently of its GAP activity (38). Recently, RacGAP1 has also been implicated in regulating the localization and transcriptional activity of signal transducer and activation of transcription (STAT) proteins (39,40), a family of proteins that have been strongly implicated in the stromal decidualization response and embryo implantation (41). Here, we have shown that hESC Rac-GAP1 levels are down-regulated in response to human embryos and that this correlates with an increase in Rac1 activity observed in hESCs.…”

Control of the STAT6–BCL6 Antagonism by SWAP-70 Determines IgE Production

“…Control of cytoplasmic/ nuclear shuttling may depend on diverse mechanisms, varying for specific STAT proteins, including methylation (31), association with proteins carrying nuclear localization signals (29), serine phosphorylation (32) and rearrangements of cytoskeletal components (33,34). Nuclear translocation of some STAT proteins, such as STAT5 and STAT3, depends on their association with the GTPase activating protein, MgcRacGAP, and requires Rac1 (35,36). Considering the cytoplasmic interaction of SWAP-70 with Rac and the function of SWAP-70 in cytoplasmic cytoskeletal rearrangements described by us (37-40), we speculated that SWAP-70 may participate in the transport of STAT6 into the nucleus.…”

PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1

“…While STAT3 requires facilitated import into the nucleus via importin ␣ 5 (27), molecules other than importins, such as Rac1, are specifically required for the nuclear translocation of STAT3 (46). Kawashima et al (21) show that activated Rac1 is specifically required for the interaction of phospho-STAT5A with importins. In our studies, PDGF treatment results in Rac1 and STAT3 nuclear colocalization, suggesting that Rac1 not only facilitates nuclear import of STAT3 but also enters the nucleus with it.…”

“…Additionally, we have previously determined that STAT3 activation is directly regulated by the small GTPase Rac1 in fibroblasts (44). Recent studies by us and others have shown that Rac1 contributes to maximal STAT3 activation, transcriptional activity, and nuclear translocation and that the STAT3/Rac1 interaction is important in STAT3 function (21,36,37,44,46,47). However, the results regarding the direct regulation of STAT3 by Rac1 have been somewhat contradictory, likely due to the fact that the studies have used different cell types and stimuli, and have often relied on overexpression studies using dominant negative forms of Rac1 (DnRac1).…”