SRGAP2
Description
The SRGAP2 (SLIT-ROBO Rho GTPase activating protein 2) is a protein-coding gene located on chromosome 1.
SRGAP2 (SLIT-ROBO Rho GTPase-activating protein 2), also known as Formin-binding protein 2 (FNBP2), is a mammalian protein encoded by the SRGAP2 gene in humans. It is involved in neuronal migration and differentiation and plays a crucial role in synaptic development, brain mass, and the number of cortical neurons. Downregulation of srGAP2 inhibits cell-cell repulsion and enhances cell-cell contact duration. SRGAP2 dimerizes through its F-BAR domain. SRGAP2C, a shortened version found in early hominins and humans that only has the F-BAR domain, antagonizes its action. It slows the maturation of some neurons and increases neuronal spine density.
SRGAP2 is one of 23 genes known to be duplicated in humans but not other primates. SRGAP2 has been duplicated three times in the human genome in the past 3.4 million years: one duplication 3.4 million years ago (mya) called SRGAP2B, followed by two that copied SRGAP2B 2.4 mya into SRGAP2C and ~1 mya into SRGAP2D. All three duplications are also present in Denisovans and Neanderthals. They are shortened in the same manner, keeping the F-box domain but losing the RhoGAP and SH3 domains. All humans possess SRGAP2C. SRGAP2C inhibits the function of the ancestral copy, SRGAP2A, by heterodimerization and allows faster migration of neurons by interfering with filopodia production as well as slowing the rate of synaptic maturation and increasing the density of synapses in the cerebral cortex.
SRGAP2 is a postsynaptic RAC1 GTPase activating protein (GAP) that plays a key role in neuronal morphogenesis and migration, particularly during the development of the cerebral cortex. It regulates the maturation and density of both excitatory and inhibitory synapses in cortical pyramidal neurons. SRGAP2 limits the density of these synapses through its specific GTPase activating activity towards RAC1, but promotes their maturation by binding to postsynaptic scaffolding proteins HOMER1 at excitatory synapses and GPHN at inhibitory synapses. This protein acts by binding and deforming membranes, thus regulating actin dynamics to control cell migration and differentiation. It promotes cell repulsion and contact inhibition of locomotion by localizing to protrusions with curved edges and controlling the duration of RAC1 activity in these protrusions. SRGAP2 may also play a role in cell migration in non-neuronal cells by regulating the formation of lamellipodia and filopodia.
SRGAP2 is also known as ARHGAP34, FNBP2, SRGAP2A, SRGAP3.
