RACGAP1 explained

Rac GTPase-activating protein 1 is an enzyme that in humans is encoded by the RACGAP1 gene.^[1]

Function

Rho GTPases control a variety of cellular processes. There are 3 subtypes of Rho GTPases in the Ras superfamily of small G proteins: RHO (see MIM 165370), RAC (see RAC1; MIM 602048), and CDC42 (MIM 116952). GTPase-activating proteins (GAPs) bind activated forms of Rho GTPases and stimulate GTP hydrolysis. Through this catalytic function, Rho GAPs negatively regulate Rho-mediated signals. GAPs may also serve as effector molecules and play a role in signaling downstream of Rho and other Ras-like GTPases.[supplied by OMIM].^[2] Over-expression of RACGAP1 is observed in multiple human cancers including breast cancer,^[3] gastric cancer^[4] and colorectal cancer.^[5] Evidence show that RACGAP1 can modulate mitochondrial quality control by stimulating mitopahy and mitochondrial biogenesis in breast cancer.^{[6] [7]} Knocking out RACGAP1 in vitro using CRISPR/Cas9 leads to cytokinesis failure.^[8]

Interactions

RACGAP1 has been shown to interact with ECT2,^[9] Rnd2^[10] and SLC26A8.^[11]

During cytokinesis, RACGAP1 has been shown to interact with KIF23 to form the centralspindlin complex.^[12] This complex is essential for the formation of the central spindle. RACGAP1 also interacts with PRC1 to stabilize and maintain the central spindle as anaphase proceeds.^[13] RACGAP1 can also interact with ECT2 during anaphase of cytokinesis, loss of RACGAP1 leads to cytokinesis failure.^[14]

References

Further reading

• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Gerwins P, Blank JL, Johnson GL . Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway . The Journal of Biological Chemistry . 272 . 13 . 8288–95 . March 1997 . 9079650 . 10.1074/jbc.272.13.8288 . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Nagata K, Puls A, Futter C, Aspenstrom P, Schaefer E, Nakata T, Hirokawa N, Hall A . The MAP kinase kinase kinase MLK2 co-localizes with activated JNK along microtubules and associates with kinesin superfamily motor KIF3 . The EMBO Journal . 17 . 1 . 149–58 . January 1998 . 9427749 . 1170366 . 10.1093/emboj/17.1.149 .
• Tapon N, Nagata K, Lamarche N, Hall A . A new rac target POSH is an SH3-containing scaffold protein involved in the JNK and NF-kappaB signalling pathways . The EMBO Journal . 17 . 5 . 1395–404 . March 1998 . 9482736 . 1170487 . 10.1093/emboj/17.5.1395 .
• Abo A, Qu J, Cammarano MS, Dan C, Fritsch A, Baud V, Belisle B, Minden A . PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia . The EMBO Journal . 17 . 22 . 6527–40 . November 1998 . 9822598 . 1171000 . 10.1093/emboj/17.22.6527 .
• Zuber J, Tchernitsa OI, Hinzmann B, Schmitz AC, Grips M, Hellriegel M, Sers C, Rosenthal A, Schäfer R . A genome-wide survey of RAS transformation targets . Nature Genetics . 24 . 2 . 144–52 . February 2000 . 10655059 . 10.1038/72799 . 21887748 .
• John R. Falck . Das B, Shu X, Day GJ, Han J, Krishna UM, Falck JR, Broek D . Control of intramolecular interactions between the pleckstrin homology and Dbl homology domains of Vav and Sos1 regulates Rac binding . The Journal of Biological Chemistry . 275 . 20 . 15074–81 . May 2000 . 10748082 . 10.1074/jbc.M907269199 . free .
• Nagase T, Kikuno R, Ishikawa K, Hirosawa M, Ohara O . Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 7 . 2 . 143–50 . April 2000 . 10819331 . 10.1093/dnares/7.2.143 . free .
• Kawashima T, Hirose K, Satoh T, Kaneko A, Ikeda Y, Kaziro Y, Nosaka T, Kitamura T . MgcRacGAP is involved in the control of growth and differentiation of hematopoietic cells . Blood . 96 . 6 . 2116–24 . September 2000 . 10979956 . 10.1182/blood.V96.6.2116 .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Hirose K, Kawashima T, Iwamoto I, Nosaka T, Kitamura T . MgcRacGAP is involved in cytokinesis through associating with mitotic spindle and midbody . The Journal of Biological Chemistry . 276 . 8 . 5821–8 . February 2001 . 11085985 . 10.1074/jbc.M007252200 . free .
• Caloca MJ, Wang H, Delemos A, Wang S, Kazanietz MG . Phorbol esters and related analogs regulate the subcellular localization of beta 2-chimaerin, a non-protein kinase C phorbol ester receptor . The Journal of Biological Chemistry . 276 . 21 . 18303–12 . May 2001 . 11278894 . 10.1074/jbc.M011368200 . free .
• Toure A, Morin L, Pineau C, Becq F, Dorseuil O, Gacon G . Tat1, a novel sulfate transporter specifically expressed in human male germ cells and potentially linked to rhogtpase signaling . The Journal of Biological Chemistry . 276 . 23 . 20309–15 . June 2001 . 11278976 . 10.1074/jbc.M011740200 . free .
• Mishima M, Kaitna S, Glotzer M . Central spindle assembly and cytokinesis require a kinesin-like protein/RhoGAP complex with microtubule bundling activity . Developmental Cell . 2 . 1 . 41–54 . January 2002 . 11782313 . 10.1016/S1534-5807(01)00110-1 . free .
• Vikis HG, Li W, Guan KL . The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding . Genes & Development . 16 . 7 . 836–45 . April 2002 . 11937491 . 186329 . 10.1101/gad.966402 .
• Kitamura T, Kawashima T, Minoshima Y, Tonozuka Y, Hirose K, Nosaka T . Role of MgcRacGAP/Cyk4 as a regulator of the small GTPase Rho family in cytokinesis and cell differentiation . Cell Structure and Function . 26 . 6 . 645–51 . December 2001 . 11942621 . 10.1247/csf.26.645 . free .
• Côté JF, Vuori K . Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity . Journal of Cell Science . 115 . Pt 24 . 4901–13 . December 2002 . 12432077 . 10.1242/jcs.00219 . free .
• Jantsch-Plunger V, Gönczy P, Romano A, Schnabel H, Hamill D, Schnabel R, Hyman AA, Glotzer M . CYK-4: A Rho family gtpase activating protein (GAP) required for central spindle formation and cytokinesis . The Journal of Cell Biology . 149 . 7 . 1391–404 . June 2000 . 10871280 . 2175131 . 10.1083/jcb.149.7.1391 .

Notes and References

1. Touré A, Dorseuil O, Morin L, Timmons P, Jégou B, Reibel L, Gacon G . MgcRacGAP, a new human GTPase-activating protein for Rac and Cdc42 similar to Drosophila rotundRacGAP gene product, is expressed in male germ cells . The Journal of Biological Chemistry . 273 . 11 . 6019–23 . March 1998 . 9497316 . 10.1074/jbc.273.11.6019 . free .
2. Web site: Entrez Gene: RACGAP1 Rac GTPase activating protein 1.
3. Ren K, Zhou D, Wang M, Li E, Hou C, Su Y, Zou Q, Zhou P, Liu X . RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis . Experimental Cell Research . 400 . 1 . 112493 . March 2021 . 33485843 . 10.1016/j.yexcr.2021.112493 . 231701513 .
4. Saigusa S, Tanaka K, Mohri Y, Ohi M, Shimura T, Kitajima T, Kondo S, Okugawa Y, Toiyama Y, Inoue Y, Kusunoki M . Clinical significance of RacGAP1 expression at the invasive front of gastric cancer . Gastric Cancer . 18 . 1 . 84–92 . January 2015 . 24615626 . 10.1007/s10120-014-0355-1 . 13008506 .
5. Imaoka H, Toiyama Y, Saigusa S, Kawamura M, Kawamoto A, Okugawa Y, Hiro J, Tanaka K, Inoue Y, Mohri Y, Kusunoki M . RacGAP1 expression, increasing tumor malignant potential, as a predictive biomarker for lymph node metastasis and poor prognosis in colorectal cancer . Carcinogenesis . 36 . 3 . 346–54 . March 2015 . 25568185 . 10.1093/carcin/bgu327 . free .
6. Ren K, Zhou D, Wang M, Li E, Hou C, Su Y, Zou Q, Zhou P, Liu X . RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis . Experimental Cell Research . 400 . 1 . 112493 . March 2021 . 33485843 . 10.1016/j.yexcr.2021.112493 . 231701513 .
7. Zhou D, Ren K, Wang M, Wang J, Li E, Hou C, Su Y, Jin Y, Zou Q, Zhou P, Liu X . Long non-coding RNA RACGAP1P promotes breast cancer invasion and metastasis via miR-345-5p/RACGAP1-mediated mitochondrial fission . Molecular Oncology . 15 . 2 . 543–559 . February 2021 . 33252198 . 7858103 . 10.1002/1878-0261.12866. 1574-7891 .
8. 2021-03-01. RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis. Experimental Cell Research. en. 400. 1. 112493. 10.1016/j.yexcr.2021.112493. 0014-4827. Ren . Kehan . Zhou . Danmei . Wang . Meili . Li . Ermin . Hou . Chenjian . Su . Ying . Zou . Qiang . Zhou . Ping . Liu . Xiuping . 33485843 . 231701513 .
9. Ren K, Zhou D, Wang M, Li E, Hou C, Su Y, Zou Q, Zhou P, Liu X . RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis . Experimental Cell Research . 400 . 1 . 112493 . March 2021 . 33485843 . 10.1016/j.yexcr.2021.112493 . 231701513 .
10. Naud N, Touré A, Liu J, Pineau C, Morin L, Dorseuil O, Escalier D, Chardin P, Gacon G . Rho family GTPase Rnd2 interacts and co-localizes with MgcRacGAP in male germ cells . The Biochemical Journal . 372 . Pt 1 . 105–112 . May 2003 . 12590651 . 1223378 . 10.1042/BJ20021652 .
11. Toure A, Morin L, Pineau C, Becq F, Dorseuil O, Gacon G . Tat1, a novel sulfate transporter specifically expressed in human male germ cells and potentially linked to rhogtpase signaling . The Journal of Biological Chemistry . 276 . 23 . 20309–20315 . June 2001 . 11278976 . 10.1074/jbc.M011740200 . free .
12. Glotzer M . Cytokinesis: centralspindlin moonlights as a membrane anchor . Current Biology . 23 . 4 . R145-7 . February 2013 . 23428321 . 10.1016/j.cub.2013.01.006 . free . 2013CBio...23.R145G .
13. Lee KY, Esmaeili B, Zealley B, Mishima M . Direct interaction between centralspindlin and PRC1 reinforces mechanical resilience of the central spindle . Nature Communications . 6 . 7290 . June 2015 . 26088160 . 4557309 . 10.1038/ncomms8290 . 2015NatCo...6.7290L .
14. Ren K, Zhou D, Wang M, Li E, Hou C, Su Y, Zou Q, Zhou P, Liu X . RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis . Experimental Cell Research . 400 . 1 . 112493 . March 2021 . 33485843 . 10.1016/j.yexcr.2021.112493 . 231701513 .