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Review
. 2024 Dec 24;15(1):3.
doi: 10.3390/biom15010003.

The Expression Regulation and Cancer-Promoting Roles of RACGAP1

Jiacheng Lin  1   2 , Yuhao Zhu  1   2 , Zhaoping Lin  1   2 , Jindong Yu  1   2 , Xiaobing Lin  1   2 , Weiyuan Lai  1   2 , Beibei Tong  1   2 , Liyan Xu  2   3 , Enmin Li  1   2 , Lin Long  1   2   3
Affiliations
Review

The Expression Regulation and Cancer-Promoting Roles of RACGAP1

Jiacheng Lin et al. Biomolecules. .

Abstract

RACGAP1 is a Rho-GTPase-activating protein originally discovered in male germ cells to inactivate Rac, RhoA and Cdc42 from the GTP-bound form to the GDP-bound form. GAP has traditionally been known as a tumor suppressor. However, studies increasingly suggest that overexpressed RACGAP1 activates Rac and RhoA in multiple cancers to mediate downstream oncogene overexpression by assisting in the nuclear translocation of signaling molecules and to promote cytokinesis by regulating the cytoskeleton or serving as a component of the central spindle. Contradictorily, it was also reported that RACGAP1 in gastric cancer could inactivate Rac and RhoA. In addition, studies have revealed that RACGAP1 can be a biomarker for prognosis, and its role in reducing doxorubicin sensitivity poses difficulties for treatment, while the current drug targets mainly focus on its downstream molecule. This article mainly reviews the expression regulation of RACGAP1 and its cancer-promoting functions through oncogene expression mediation and Rho-GTPase activation.

Keywords: ECT2; RACGAP1; Rho-GTPases; STAT3.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
RACGAP1 promotes cancer through the Hippo pathway and JAK/STAT pathway. In the Hippo pathway, the phosphorylated form of MST1/2 activates LAST1/2 via phosphorylation. YAP can be deactivated by the activated form of LAST when phosphorylated. YAP in the non-phosphorylated state can enter the nucleus, bind to the promoter region of TPR with TEAD and promote its transcription. TPR, RACGAP1 and AURKB form complexes that promote spindle formation. Moreover, RACGAP1 inhibits the Hippo pathway by promoting the inactivation of LAST1/2 through F-actin. RACGAP1 forms a ternary complex together with STAT3 and Rac1 to phosphorylate STAT3, and accomplishes the nuclear transport of STAT3 as a nuclear chaperone. RACGAP1 binds JAK2 to enable the phosphorylation of STAT3 by JAK2. Rac1 and p-STAT3 activate the nuclear localization signal (NLS) in RACGAP1 so that it can promote the nuclear translocation and the transcriptional activity of p-STAT3. RACGAP1 can inactivate Rac1, but after binding with APPL2, it cannot inactivate Rac1.
Figure 2
Figure 2
RACGAP1 can activate Rho-GTPases. (a) RACGAP1 inhibits Rac1, Cdc42 and RhoA. (b) Phosphorylated RACGAP1 can activate Rac1. (c) RACGAP1 can activate RhoA in hepatocellular carcinoma. (d) RACGAP1 can form a complex with Rac1 and STAT3, and with ECT and MKLP1, the latter complex of which can activate RhoA. (e) In NIH3T3 cells, Rac1 can inhibit RhoA. (f) In Swiss 3T3 fibroblasts, RhoA can activate Rac1.
Figure 3
Figure 3
RACGAP1 binding ECT2 to promotes actomyosin ring formation. Plk phosphorylates RACGAP1 at 2 sites so that RACGAP1 binds to ECT2 with the help of MKLP1, and the complex activates RhoA, Myosin II and ERK. PP2A-B′ can bind to RACGAP1 to break the interaction between RACGAP1 and ECT2.
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