RACGAP1 gene

The RACGAP1 gene (RACGAP1 stands for: Rac GTPase Activating Protein 1) is a protein-coding gene located on chromosome 12q13.12. This gene encodes a GTPase-activating protein (short: GAP), which is a component of the centralspindlin complex. GAP is a regulatory protein that accelerates the activity of so-called GTPases.

Alternatively spliced transcript variants have been found for this gene. There is a pseudogene for this gene on chromosome 12.

The GTPase-activating protein binds activated forms of Rho-GTPases and stimulates GTP hydrolysis, resulting in negative regulation of Rho-mediated signaling.

The GTPase-activating protein plays a regulatory role in cytokinesis, cell growth and differentiation.

Diseases associated with RACGAP1 include:

Autosomal recessive and congenital dyserythropoietic anemia type Iiib.

What are GTPases: GTPases are enzymes (often small G-proteins such as Ras, Rho, Rab, etc.) that act as molecular switches in the cell. They bind guanosine triphosphate (GTP) and are active in the GTP-bound state. They become inactive when GTP is hydrolyzed to GDP (guanosine diphosphate). Ras-GAP regulates the activity of the Ras protein, which plays a role in many signaling pathways (e.g. cell growth). Misregulation can lead to cancer.

General functions of GAPs: GAPs accelerate this hydrolysis reaction. This means:

• GTPase + GTP → (slow) → GTPase + GDP + Pi
• GTPase + GTP + GAP → (fast) → GTPase + GDP + Pi

Function:

• GAPs inactivate GTPases faster by enhancing their intrinsic GTPase activity.
• They therefore have a negative regulatory effect on signaling pathways that run via GTPases.

The GAP protein binds sequentially to ECT2 and RAB11FIP3, which regulates cleavage furrow ingression and abscission during cytokinesis . It plays a key role in the control of cell growth and differentiation of hematopoietic cells through mechanisms other than regulation of Rac GTPase activity (Simon GC et al. 2008).

The GAP protein1 plays a crucial role in erythropoiesis (Wontakal SN et al. 2022). It is also involved in the regulation of growth-related processes in adipocytes and myoblasts. GAP protein1 is thought to be involved in the regulation of spermatogenesis and the RACGAP1 signaling pathway in neuronal proliferation. It shows strong GAP activity (GTPase activation) towards CDC42 and RAC1 and less towards RHOA. It is essential for the early stages of embryogenesis. May play a role in the regulation of cortical activity by RHOA during cytokinesis. Possibly involved in the regulation of sulfate transport in male germ cells.

1. Kawashima T et al. (2000) MgcRacGAP is involved in the control of growth and differentiation of hematopoietic cells. Blood 96:2116-2124.
2. Simon GC et al. (2008) Sequential Cyk-4 binding to ECT2 and FIP3 regulates cleavage furrow ingression and abscission during cytokinesis. EMBO J 27:1791-803.
3. Wontakal SN et al. (2022) RACGAP1 variants in a sporadic case of CDA III implicate the dysfunction of centralspindlin as the basis of the disease. Blood 139:1413-1418.