RACGAP1 (Rac GTPase activating protein 1)

2016-02-01   Alexios Strimpakos , Dimitrios Sampaziotis , Amanda Psyrri 


CYK4,HsCYK-4,ID-GAP,MgcRacGAP,Male Germ Cell RACGAP,Protein CYK4 Homolog,KIAA1478,ID-GAP,RCGAP1 (Toure A et al.., 1998, Toure A et al.., 2001, Burkard ME et al., 2009)


Review on RACGAP1, with data on DNA, on the protein encoded, and where the gene is implicated.


Atlas Image
A schematic illustration of RACGAP1 gene The RACGAP1 gene is shown with red bar and it is flanked by AQP6 and AQP5 genes on the left side and ASIC1 and SMARCD1 genes on the right side. RACGAP1s location is on 12q13.12, and it has 22 exons (NCBI).


According to NCBI Map Viewer, RACGAP1 maps to NC_000012.12 in the region between 49961496 and 50100711 on the minus strand and spans 56,214 bases. The total number of exons is 22. As reported by SABiosciences database, the transcription factor binding sites, in the RACGAP1 gene promoter, are: STAT3, FOXO1, GATA1, TBP, FOXD3, FOXO4, SRY, REPIN1 (AP-4).


RACGAP1 gene has 12 alternative transcript variants, which encode 4 isoforms of Rac GTPase activating protein 1. The locus of the reference variant (variant 1) is in NM_013277 and it has 3361bp. Variant 2 lacks an exon and contains an alternate exon in the 5 UTR, while variant 3 lacks two exons and uses an alternate splice site in the 5 UTR, variant 4 lacks two exons in the 5 UTR, variant 5 lacks two exons and contains an alternate exon in the 5 UTR and variant 6 lacks two exons and uses two alternate splice sites in the 5 UTR. Variants 7, 8 and 9 lack two exons and use an alternate splice site in the 5 UTR. All the transcript variants from 1 to 9 encode for isoform a. The 10th variant lacks three exons in the 5 region and initiates translation at a downstream start codon compared to variant 1. Its encoded isoform b has a shorter N-terminus than isoform a. The 11th variant lacks two exons, contains an alternate exon and uses an alternate splice site in the 5 region. It initiates translation at an alternate start codon. Its encoded isoform c has a longer N-terminus than isoform a. Lastly, variant 12 lacks three exons in the 5 region and initiates translation at an alternate downstream start codon. The encoded isoform d has a distinct N-terminus and is shorter than isoform a. Transcription is regulated by STAT3, FOXO1, GATA-1, TBP, FOXD3, FOXO4, SRY and AP-4 binding sites (NCBI database).


FKSG42 is a RACGAP1 pseudogene as reported by HGNC. It is located in 12q12 chromosome and it has 1 exon.



RACGAP1 protein plays an important role in the Rho GTPase activation cycle. In fact, it binds activated forms of Rho GTPases and stimulates GTP hydrolysis. Thus, it inhibits Rho-mediated signals. Regarding RACGAP1 protein function, it has a regulatory role in the starting of cytokinesis, regulates spermatogenesis and proliferation of neuronal cells, as well as it controls cell growth and differentiation of hematopoietic cells (Boguski M.S. et al., 1993; Hamanaka R. et al., 1994). Lately, it was found that high levels of RACGAP1 is correlated with a worse prognosis in patients with high grade meningiomas (Brennan IM et al., 2007), while Wang SM et al. showed that RACGAP1 upregulation is associated with relapse of hepatocellular cancer (Wang SM et al., 2011).
Atlas Image
The Crystal Structure Of The Human Rac GTPase Activating Protein 1 (RACGAP1) (PROTEIN DATA BANK)


According to Swiss Prot database the protein contains 632 amino acids and its molecular mass is 71027 Da. About proteins structure, it is a heterotetramer of two of RACGAP1 and KIF23 ID: 41068> (Kinesin Family membre 23) molecules. It is found in the centralspindlin complex, a motor complex required for the assembly of the mitotic spindle (Nature Reviews Molecular Cell Biology, 2009). It is associated with alpha-, beta- and gamma-tubulin and microtubules. The protein interacts via its Rho-GAP domain with RND2 (Rho family GTPase 2) and PRC1 (Protein Regulator of Cytokinesis). Its GAP activity towards CDC42 (Cell Division Cycle42 effector protein) is inhibited by interaction with PRC1 in vitro, which may be important for maintaining a normal spindle morphology. Furthermore, RACGAP1 associates with AURKB (Aurora Kinase B) during M phase and interacts with SLC26A8 (Solute Carrier family 26 member 8) via its N-terminus and RAB11FIP3 (RAB11 Family Interacting Protein 3). During anaphase and cytokinesis, the protein binds to ECT2 (Epithelial Cell Transforming 2) in a microtubule-dependent manner and it is enhanced by phosphorylation by PLK1 (Polo-like Kinase 1). Lastly, it interacts directly with KIF23.


It is highly expressed in the testis, thymus, placenta, gastrointestinal tract, urinary tract, uterus, cervix, skin, tonsil, nasopharynx, bone marrow and lymph nodes. It is found at lower levels in spleen and peripheral blood lymphocytes. In testis, RACGAP1 expression is restricted to germ cells with the highest levels of expression found in spermatocytes. Its expression is monitored during the cell cycle and it peaks at G2/M phase (Toure A et al., 1998; Toure A et al., 2001; Naud N et al., 2003; Zhang P et al., 2015).


RACGAP1 colocalizes with RND2 in Golgi-derived proacrosomal vesicles and the acrosome. During interphase, it is localized to the nucleus and cytoplasm along with microtubules, while in anaphase it is organized to the central spindle and in telophase and cytokinesis to the midbody. Colocalization of RACGAP1 with RhoA occurs at the myosin contractile ring during cytokinesis and with ECT2 at the mitotic spindles during anaphase/metaphase, at the cleavage furrow during telophase, and to the midbody at the end of cytokinesis. Lastly, it neighbours with CDC42 to spindle microtubules from prometaphase to telophase (Mishima M et al., 2002).


MgcRacGAP is a component of the central spindlin complex that serves as a microtubule-dependent and Rho-mediated signaling, required for the myosin contractile ring formation during the cytokinesis. To specify, it helps for a proper attachment of the midbody to the cell membrane during cytokinesis. GAP1 plays also key role in controlling cell growth and differentiation of hematopoietic cells, adipocytes and myoblasts. It may regulate the cell proliferation in the nervous system as well as the sulfate transport in male germ cells. In addition, MgcRacGAP, by inhibiting the activity of RAC1 and CDC42, which act on the microtubule and actin cytoskeleton, controls cell proliferation, adhesion and motility. It may play a role in regulating cortical activity throughRHOA-mediated signals during cytokinesis. At last, it is found to be essential for the early stages of embryogenesis (Toure A et al., 1998; Kawashima T et al., 2000; Hirose K et al., 2001; Yuce O et al., 2005).


According to NCBI, the RACGAP1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, and frog.



The mammalian Polo-like kinase PLK1 (Hamanaka R et al., 1994) was shown recently to be an essential activator of RhoA (Brennan IM et al., 2007; Burkard ME et al., 2007; Petronczki et al., 2007; Santamaria et al., 2007). Inhibition of PLK1 prevents ECT2 association with HsCyk-4 (alias of RACGAP1) and blocks its recruitment to the central spindle (Brennan IM et al., 2007; Burkard ME et al., 2007; Petronczki et al., 2007; Santamaria et al., 2007), proposing that PLK1 might serve as a stimulatory kinase. Benjamin A. Wolfe et al., examined the mechanism by which PLK1 stimulates association between ECT2 and HsCyk-4 during anaphase to trigger the cytokinesis (Benjamin A. Wolfe et al., 2009). In the meanwhile, Lowery DM and colleagues found that the N terminus (Nt) of HsCyk-4 contains seven consensus motifs for PLK1 phosphorylation (Lowery DM et al., 2005). Benjamin et al., trying to determine which sites are phosphorylated by PLK1, confirmed that only peptides containing amino acids 139-174 of HsCyk-4 did so. Within this region, they took up four hypothetical PLK1 phosphorylation sites (Ser149, Ser157, Ser164, and Ser170), which are well conserved across species, and they altered them. Mutation of any of these four residues was insufficient on its own to prevent PLK1-stimulated binding. The results show that, in vitro phosphorylation of HsCyk-4-4A (amino acids 111-188) by PLK1 was dramatically reduced. Conversely, they mutated these four serine residues to Asp (HsCyk-4-4D) so as to mimic the phosphorylated state, and generated a form of HsCyk-4 able to associate with ECT2-BRCT even in the absence of PLK1 phosphorylation.Based on these results they conclude that PLK1 phosphorylates multiple serine residues in the N terminus of HsCyk-4 in vitro, thereby stimulating its association with ECT2.

Implicated in

Entity name
Meningiomas are a diverse set of tumors arising from meninges, the membranous layers covering the brain and the spinal cord (Cushing H, 1922). Meningiomas specifically derive from the arachnoid granulations of the arachnoid matter (Buetow MP et al., 1991). These tumors are usually benign in nature and slowly growing; however, a small percentage are malignant (Goldsmith BJ et al., 1994). The classification of mengiomas is based upon the WHO classification system: Grade I (Benign) 90% - meningothelial, fibrous, transitional, psammomatous, angioblastic, Grade II (Atypical) 7% - chordoid, clear cell, atypical (includes brain invasion), Grade III (Anaplastic/malignant) 2% - papillary, rhabdoid, anaplastic (most aggressive). Most meningiomas produce no symptoms throughout a persons life, and if accidentantly found, require no treatment other than periodic observation. Typically, symptomatic meningiomas are treated with either radiosurgery or conventional surgery.
Ke HL et al. did a research on how RACGAP1 expression is correlated in the meningiomas (Ke HL et al.., 2013). The results showed a higher RACGAP1 expression in Grade III mengingioma comparing to Grade I. Higher levels of RACGAP1 mRNA were significantly correlated with tumor size, higher Simpson grade, histological type and clinical course (P < 0.05). Additionally, patients with high levels of RACGAP1 mRNA had a significantly worse survival than the lower level ones (P = 0.008). Upon these results, the researchers suggested that RACGAP1 may be used as a potential predictive biomarker for disease aggressiveness and patients prognosis.
Entity name
Hepatocellular carcinoma
Hepatocellular carcinoma (HCC), also called malignant hepatoma, is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitis infection (hepatitis B or C) or cirrhosis. The clinical manifestations of HCC are usually jaundice, ascites, blood clotting abnormalities, loss of appetite, unintentional weight loss, abdominal pain, especially in the right upper quadrant, nausea, vomiting, or tiredness. Prognosis and treatment options for HCC depend on staging but also on other factors such tumor grade, Child-Pugh score and overall patients performance status and comorbidities. High-grade tumors will have a poor prognosis, while low-grade tumors may go unnoticed for many years (Naud N et al., 2003)
It has been proved that relapse of Hepatocellular Carcinoma (HCC) increases with higher HBV viral load (Yu SJ et al., 2014). Wang SM et al., proved that high RACGAP1 expression associates with high risk of relapse of HBV-positive HCC patients (Wang SM et al., 2011). According to their research, silencing of RACGAP1 in Hep3B and MHCC97-H, in cancer cells with high endogenous RACGAP1 expression, inhibited cell migration and invasion. This outcome suggests that RACGAP1 besides being an independent informative prognostic biomarker, it could also be a potential molecular target for designing therapeutic strategies for HCC.
Entity name
Colorectal cancer
Colorectal cancer is the development of cancer in the large bowel. Signs and symptoms may include melena (black stools), a change in bowel habits, pain, weight loss, cachexia, or persistent fatigue. Treatments available for colorectal cancer include surgery, radiation therapy, chemotherapy, targeted therapy or combination of above depending on the disease site and stage. Cancers confined to the wall of the colon are usually curable with surgery while cancer that has spread distantly are usually incurable. In very advanced stages management might simply focus on quality of life and symptoms control (National Cancer Institute, 2014).
RACGAP1 plays a key role in regulating various cellular functions including cytokinesis, transformation, invasive migration and metastasis. In the study of Imaoka H et al., the function and clinical significance of RACGAP1 expression in colorectal cancer (CRC) was investigated (Imaoka H et al., 2015). Reduced RACGAP1 expression by siRNA in CRC cell lines showed significantly decreased cellular proliferation, migration and invasion whereas increased expression of RACGAP1 was highly associated with worse prognosis. In multivariate analyses, the researchers found that high levels of RACGAP1 was an independent prognostic biomarker for lymph node metastasis and worse disease-free and relapse free survival in CRC.
Entity name
Gastric cancer
Stomach cancer, also known as gastric cancer, develops from the lining of the stomach. Early symptoms may include heartburn, upper abdominal pain, nausea and loss of appetite. Later signs and symptoms may include weight loss, vomiting, difficulty swallowing, and melena. The cancer may spread from the stomach to other parts of the body, particularly the lymph nodes, liver, lungs, peritoneum or bones etc. Worldwide, stomach cancer is the fifth leading cause of cancer and the third leading cause of death from cancer. Regarding its management, this disease is not usually curable unless it is found at a very early stage. Unfortunately, the majority of patients are diagnosed when the disease has already become advanced. Treatment options include surgery, chemotherapy, radiation therapy (National Cancer Institute, 2014) and lately biological therapy and immunotherapy.
Saigusa S et al. studied the clinical significance of RACGAP1 expression at the invasive form of gastric cancer (Saigusa S et al., 2015). Patients with positive RACGAP1 expression at the invasive form, had significantly poorer prognosis than those without expression (P < 0.0001). In the multivariate analysis, lymph node metastasis (P = 0.0106), distant metastasis (P = 0.0012) and positive RACGAP1 expression (P = 0.001) were independent prognostic factors. Based on these results, researchers conclude that RACGAP1 expression may play a crucial rule in the progression of gastric cancer.
Entity name
Melanoma is a type of cancer that develops from the melanine-containing skin cells, known as melanocytes. Early signs of melanoma are changes to the shape or color of an existing mole or, in the case of nodular melanoma, the appearance of a new lump anywhere on the skin. At later stages, the mole may itch, ulcerate or bleed (National Cancer Institute, 2015). Melanomas are usually caused by DNA damage resulting from long-standing exposure to ultraviolet (UV) light from the sun. Confirmation of the clinical diagnosis is based on a skin biopsy. Treatment of melanoma may include surgery, chemotherapy, immunotherapy and radiotherapy, depending again on disease and patients stage and status.
Melanoma cell migration across vascular endothelial cells is crucial for tumor metastasis. According to Zhang P et al., RACGAP1-driven focal adhesion formation, promotes melanoma cells to migrate through vascular endothelium by causing adherens junction disassembly (Zhang P et al., 2015). After, depletion of RACGAP1 with RACGAP1-targeting siRNA or overexpression of RACGAP1 mutant (T249A), melanoma cell transendothelial migration and disorganization of adherens junctions was reduced. In addition, RACGAP1 promoted the activation of RhoA, FAK, PXN (paxillin) and triggered focal adhesion formation and cytoskeletal rearrangement. By overexpressing FRNK (FAK-related non-kinase) in endothelium, they proved that RACGAP1 damages the endothelial barrier and facilitates melanoma transmigration in a focal adhesion-dependent manner.


Pubmed IDLast YearTitleAuthors
82592091993Proteins regulating Ras and its relatives.Boguski MS et al
174763312007Polo-like kinase controls vertebrate spindle elongation and cytokinesis.Brennan IM et al
17498511991Typical, atypical, and misleading features in meningioma.Buetow MP et al
194683022009Plk1 self-organization and priming phosphorylation of HsCYK-4 at the spindle midzone regulate the onset of division in human cells.Burkard ME et al
82832561994Postoperative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990.Goldsmith BJ et al
80185571994Cloning and characterization of human and murine homologues of the Drosophila polo serine-threonine kinase.Hamanaka R et al
110859852001MgcRacGAP is involved in cytokinesis through associating with mitotic spindle and midbody.Hirose K et al
255681852015RacGAP1 expression, increasing tumor malignant potential, as a predictive biomarker for lymph node metastasis and poor prognosis in colorectal cancer.Imaoka H et al
109799562000MgcRacGAP is involved in the control of growth and differentiation of hematopoietic cells.Kawashima T et al
235259492013Expression of RACGAP1 in high grade meningiomas: a potential role in cancer progression.Ke HL et al
78715931994GAPs for rho-related GTPases.Lamarche N et al
147294652004MgcRacGAP regulates cortical activity through RhoA during cytokinesis.Lee JS et al
156408402005Structure and function of Polo-like kinases.Lowery DM et al
236650202013Crystal structure of GTPase-activating domain from human MgcRacGAP.Matsuura A et al
117823132002Central spindle assembly and cytokinesis require a kinesin-like protein/RhoGAP complex with microtubule bundling activity.Mishima M et al
125906512003Rho family GTPase Rnd2 interacts and co-localizes with MgcRacGAP in male germ cells.Naud N et al
162474722006Phosphorylation of the cytokinesis regulator ECT2 at G2/M phase stimulates association of the mitotic kinase Plk1 and accumulation of GTP-bound RhoA.Niiya F et al
174886232007Polo-like kinase 1 triggers the initiation of cytokinesis in human cells by promoting recruitment of the RhoGEF Ect2 to the central spindle.Petronczki M et al
246156262015Clinical significance of RacGAP1 expression at the invasive front of gastric cancer.Saigusa S et al
176711602007Use of the novel Plk1 inhibitor ZK-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis.Santamaria A et al
94973161998MgcRacGAP, a new human GTPase-activating protein for Rac and Cdc42 similar to Drosophila rotundRacGAP gene product, is expressed in male germ cells.Touré A et al
112789762001Tat1, a novel sulfate transporter specifically expressed in human male germ cells and potentially linked to rhogtpase signaling.Toure A et al
218250422011Upregulation of Rac GTPase-activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma.Wang SM et al
194683002009Polo-like kinase 1 directs assembly of the HsCyk-4 RhoGAP/Ect2 RhoGEF complex to initiate cleavage furrow formation.Wolfe BA et al
161032262005An ECT2-centralspindlin complex regulates the localization and function of RhoA.Yüce O et al
252322412014Hepatitis B viral load affects prognosis of hepatocellular carcinoma.Yu SJ et al
254757282015RacGAP1-driven focal adhesion formation promotes melanoma transendothelial migration through mediating adherens junction disassembly.Zhang P et al

Other Information

Locus ID:

NCBI: 29127
MIM: 604980
HGNC: 9804
Ensembl: ENSG00000161800


dbSNP: 29127
ClinVar: 29127
TCGA: ENSG00000161800


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
MHC class II antigen presentationREACTOMER-HSA-2132295
Factors involved in megakaryocyte development and platelet productionREACTOMER-HSA-983231
Signal TransductionREACTOMER-HSA-162582
Signaling by Rho GTPasesREACTOMER-HSA-194315
Rho GTPase cycleREACTOMER-HSA-194840
Vesicle-mediated transportREACTOMER-HSA-5653656
Membrane TraffickingREACTOMER-HSA-199991
Intra-Golgi and retrograde Golgi-to-ER trafficREACTOMER-HSA-6811442
Golgi-to-ER retrograde transportREACTOMER-HSA-8856688
COPI-dependent Golgi-to-ER retrograde trafficREACTOMER-HSA-6811434

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
117823132002Central spindle assembly and cytokinesis require a kinesin-like protein/RhoGAP complex with microtubule bundling activity.214
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
167904972006Cep55, a microtubule-bundling protein, associates with centralspindlin to control the midbody integrity and cell abscission during cytokinesis.84
161298292005MgcRacGAP controls the assembly of the contractile ring and the initiation of cytokinesis.78
226832702012Cooperative activation of PI3K by Ras and Rho family small GTPases.61
157281852005Sphingosine 1-phosphate-induced mobilization of intracellular Ca2+ mediates rac activation and adherens junction assembly in endothelial cells.58
156427492005Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis.48
218250422011Upregulation of Rac GTPase-activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma.46
156774642005H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells.43
229459352012CYK4 inhibits Rac1-dependent PAK1 and ARHGEF7 effector pathways during cytokinesis.43


Alexios Strimpakos ; Dimitrios Sampaziotis ; Amanda Psyrri

RACGAP1 (Rac GTPase activating protein 1)

Atlas Genet Cytogenet Oncol Haematol. 2016-02-01

Online version: http://atlasgeneticsoncology.org/gene/46389/racgap1