Disease relevance of RACGAP1

• Multiple large blebs were observed in cells expressing MgcRacGAP R386A from the onset of anaphase to the late stage of cell division [1].
• Furthermore, inactivation of Rac by expression of the Rac GTPase-activating protein beta2-chimerin inhibited HRG-induced ERK activation, mitogenicity, and migration in breast cancer cells [2].

High impact information on RACGAP1

• (2003) establish an important connection between three regulatory molecules that coordinate this process, showing that the mitotic kinase aurora B phosphorylates MgcRacGAP to convert it to a GAP for RhoA, a small GTPase that drives cytokinesis [3].
• Recent work has identified nucleotide-exchange factors for Ral-GTPases as the newest members of the set of putative Ras 'effector molecules'. This new work has also detected two potential downstream targets of Ral proteins, a novel CDC42/Rac GTPase-activating protein and a phospholipase D [4].
• Using permeabilized cells, we find that nuclear translocation of purified p-STAT5A is dependent on the addition of GTP-bound Rac1, MgcRacGAP, importin alpha, and importin beta. 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 [5].
• We show that Rac1 and a GTPase-activating protein, MgcRacGAP, bind directly to p-STAT5A and are required to promote its nuclear translocation [5].
• We conclude that GTP-bound Rac1 and MgcRacGAP function as a nuclear transport chaperone for activated STATs [5].

Biological context of RACGAP1

• Cells overexpressing a phosphorylation mimic mutant of MgcRacGAP exhibited an abnormality of spindle morphology in the metaphase [6].
• Depletion of ECT2 or MgcRacGAP by RNA interference abolished both of the phenotypes (precocious furrowing after nocodazole release and excessive blebbing in the presence of nocodazole) [7].
• Inhibition of cyclin-dependent kinase 1 induces cytokinesis without chromosome segregation in an ECT2 and MgcRacGAP-dependent manner [7].
• Expression of a kinase-defective mutant of Aurora B disrupts cytokinesis and inhibits phosphorylation of MgcRacGAP at Ser387, but not its localization to the midbody [8].
• Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis [9].

Anatomical context of RACGAP1

• We previously identified a guanosine triphosphatase (GTPase)-activating protein (GAP) male germ cell Rac GAP (MgcRacGAP) that enhanced interleukin-6 (IL-6)-induced macrophage differentiation of murine M1 leukemia cells [10].
• Therefore we conclude that Tat1 is a novel sulfate transporter specifically expressed in spermatocytes and spermatids and interacts with MgcRacGAP in these cells [11].
• Here, we show that endomitotic megakaryocytes form midzone structures that recruit Aurora-B kinase and its substrate MgcRacGAP [12].

Associations of RACGAP1 with chemical compounds

• Unlike apoptotic blebbing, MgcRacGAP R386A-induced blebbing was not inhibited by the ROCK inhibitor Y-27632, suggesting that MgcRacGAP regulates cortical activity during cytokinesis through a novel signaling pathway [1].

Physical interactions of RACGAP1

• Two-hybrid and in vitro binding assays demonstrate that MgcRacGAP stably interacts through its NH(2)-terminal domain with the Tat1 COOH-terminal region [11].

Regulatory relationships of RACGAP1

• We conclude that MgcRacGAP controls the initiation of cytokinesis by regulating ECT2, which in turn induces the assembly of the contractile ring and triggers the ingression of the cleavage furrow [13].
• In reporter assays, the wild-type MgcRacGAP enhanced transcriptional activation of STAT3 while a GAP-domain deletion mutant (DeltaGAP) did not significantly enhance it, suggesting that the GAP domain was required for enhancement of STAT3-dependent transcription [10].
• However, how MgcRacGAP enhanced IL-6-induced differentiation remained elusive [10].
• MgcRacGAP regulates cortical activity through RhoA during cytokinesis [1].

Other interactions of RACGAP1

• Among these, Aurora B, RhoA, and the GAP MgcRacGAP have been implicated in cytokinesis, but their underlying mechanisms of action have remained unclear [8].
• Here we show that MgcRacGAP enhances IL-6-induced differentiation through enhancement of signal transducer and activator of transcription-3 (STAT3) activation [10].
• In situ hybridization studies demonstrate that Tat1 and MgcRacGAP genes are coexpressed in male germ cells at the spermatocyte stage [11].
• Intriguingly, M1 cells expressing DeltaGAP had no effect on the differentiation signal of IL-6, while forced expression of MgcRacGAP rendered M1 cells hyperresponsive to the IL-6-induced differentiation [10].
• It has been reported that Aurora-B phosphorylates MgcRacGAP to functionally convert to a RhoGAP during cytokinesis [14].

References