| 2009 |
The F-BAR domain of srGAP2 induces filopodia-like membrane protrusions (resembling I-BAR domain activity) in vivo and in vitro, negatively regulates neuronal migration, and promotes neurite outgrowth and branching. srGAP2 knockdown reduces leading process branching and increases neuronal migration rate in vivo. |
In utero electroporation knockdown and overexpression in mouse neocortex; in vitro membrane deformation assays; F-BAR domain expression in non-neuronal cells |
Cell |
High |
19737524
|
| 2012 |
SRGAP2C, a human-specific truncated paralog encoding only an F-BAR domain, dimerizes with ancestral SRGAP2 (SRGAP2A) to inhibit its function. In mouse neocortex, SRGAP2A promotes spine maturation and limits spine density; expression of SRGAP2C phenocopies SRGAP2 deficiency, leading to increased density of longer, less mature spines (neoteny) and sustained radial migration. |
Co-immunoprecipitation of SRGAP2C with SRGAP2A; in utero electroporation of SRGAP2C or SRGAP2 shRNA in mouse neocortex; spine morphology analysis |
Cell |
High |
22559944
|
| 2010 |
srGAP2 forms a complex with the formin FMNL1 (FRL1/FRLα); Rac-mediated activation of FMNL1 recruits srGAP2, whose Rac-specific GAP domain then terminates Rac signaling; additionally, the SH3 domain of srGAP2 binds the FH1 domain of FMNL1 to directly inhibit FMNL1-mediated actin severing. Both proteins co-localize to the phagocytic cup. |
Co-immunoprecipitation; in vitro actin severing assays; domain mapping; fluorescence microscopy in macrophage-derived cells |
The Journal of biological chemistry |
High |
21148482
|
| 2010 |
srGAP2 is arginine-methylated at Arg-927 by PRMT5, which binds to the N-terminal region (aa 225–538) of srGAP2. The R927A methylation mutant fails to localize to the plasma membrane leading edge, cannot rescue cell spreading, and disrupts F-BAR domain-mediated srGAP2 homodimerization, linking arginine methylation to membrane localization and cell spreading. |
Co-immunoprecipitation; domain mapping; site-directed mutagenesis (R927A); subcellular fractionation/fluorescence localization; cell spreading assays with rescue experiments |
The Journal of biological chemistry |
High |
20810653
|
| 2012 |
The F-BAR domains of srGAP1, srGAP2, and srGAP3 have distinct membrane deformation properties; F-BAR(2) (srGAP2) and F-BAR(3) induce filopodia while F-BAR(1) prevents filopodia in cortical neurons. The three F-BAR domains can heterodimerize and act synergistically in filopodia induction. F-BAR(2) membrane dynamics are partially dependent on F-actin. F-BAR(2) binds negatively charged phospholipids including PtdSer broadly, and PtdIns(4,5)P2 depletion does not displace it from the membrane. |
Expression in COS7 cells and cortical neurons; FRAP; phosphoinositide depletion; phospholipid-binding assays; Co-immunoprecipitation of heterodimerization |
Journal of cell science |
High |
22467852
|
| 2015 |
The Slit2-Robo4-srGAP2 signaling axis regulates contact inhibition of locomotion (CIL) in fibroblasts. The srGAP2 F-BAR domain senses membrane curvature to pre-localize srGAP2 to protruding edges, and srGAP2 specifically controls the duration of Rac1 activity in contact protrusions (but not contact-free protrusions) to terminate their extension after cell collision. |
FRET-based Rac1 biosensor; srGAP2 knockdown; F-BAR domain overexpression; live-cell imaging of collision events; Slit2/Robo4 perturbations |
Developmental cell |
High |
26439400
|
| 2015 |
srGAP2 uses a two-component molecular mechanism for ligand binding through its SH3 domain: one component dramatically tightens ligand association, the other moderately autoinhibits and restricts binding, achieving specificity despite weak isolated SH3-ligand affinity. |
Structural analysis; mutagenesis; binding affinity measurements (likely ITC/SPR inferred from structural study context) |
Structure |
Medium |
26365803
|
| 2017 |
SRGAP2A crystal structure reveals: (1) it homodimerizes through a large interface comprising the F-BAR domain, a newly identified F-BAR extension (Fx) domain, and RhoGAP-SH3 domains; (2) it has an unusual inverse geometry enabling membrane protrusion scaffolding in lamellipodia and dendritic spine heads; (3) SRGAP2C carries a defective Fx domain that severely compromises its solubility and membrane-scaffolding ability; (4) SRGAP2A:SRGAP2C heterodimers form but are insoluble, thereby inhibiting SRGAP2A activity; (5) the primal SRGAP2C (~3.4 Ma) is less effective at heterodimerizing with SRGAP2A than modern SRGAP2C. |
X-ray crystallography; biochemical reconstitution; cell culture expression assays; dimerization/solubility assays |
Molecular biology and evolution |
High |
28333212
|
| 2019 |
SRGAP2C and SRGAP2B are intrinsically unstable proteins in neurons; upon heterodimerization with SRGAP2A they reduce SRGAP2A protein levels in a proteasome-dependent manner. SRGAP2C-specific arginine substitutions (non-synonymous mutations) enable it to uniquely induce long-lasting increases in both excitatory and inhibitory synapse density and protracted synapse maturation throughout adulthood, unlike SRGAP2B. |
Co-immunoprecipitation; proteasome inhibitor experiments; in utero electroporation; spine/synapse density quantification over developmental time course |
Scientific reports |
High |
31822692
|
| 2017 |
SRGAP2A is primarily localized in podocytes where it co-localizes with synaptopodin, and suppresses podocyte motility through inactivation of RhoA and Cdc42 (but not Rac1). Overexpression of SRGAP2A in db/db mice via adenovirus mitigates podocyte injury and proteinuria. |
Immunofluorescence co-localization; Western blot; RhoA/Cdc42/Rac1 activity assays; podocyte migration assays; adenoviral overexpression in diabetic mouse model; zebrafish SRGAP2 knockdown |
Diabetes |
Medium |
29242313
|
| 2020 |
Srgap2 acts as a Rac1-specific GAP in osteoclasts, limiting osteoclastogenesis during TNFα-driven inflammation. Conditional knockout of Srgap2 in the myeloid lineage strongly enhances Rac1 activation in osteoclast precursors. Srgap2 also restricts osteoclast expression of the paracrine clastokine SLIT3, which promotes osteoblast differentiation. |
Myeloid-specific conditional knockout (Srgap2 f/f:LysM-Cre); Rac1 activation assays; in vitro osteoclastogenesis; bone histomorphometry; conditioned medium experiments; Western blot |
Journal of bone and mineral research |
High |
31880824
|
| 2022 |
srGAP2 acts to deactivate RhoA signaling after thrombin-induced endothelial contraction, allowing cell respreading and restoration of the endothelial barrier. Depletion of srGAP2 increases the magnitude and duration of junctional opening in response to thrombin, TNFα, and angiotensin II. srGAP2 is not required for basal barrier function in resting endothelial cells. |
srGAP2 knockdown in endothelial cells; transendothelial electrical resistance measurements; RhoA activity assays; pharmacological perturbations |
Vascular biology |
Medium |
35441126
|
| 2022 |
SRGAP2 physically interacts with mitochondrial complex I in colorectal cancer cells and positively modulates its activity. Loss of mitochondrial SRGAP2 decreases mitochondrial respiration and sensitizes CRC cells to chemotherapy, phenocopied by complex I inhibitor treatment. |
Co-immunoprecipitation of SRGAP2 with mitochondrial complex I; mitochondrial fractionation; mitochondrial respiration assays; SRGAP2 knockdown; chemosensitivity assays |
Human cell |
Medium |
36059022
|
| 2023 |
srGAP2 undergoes PKCα-mediated phosphorylation at Ser206 within the F-BAR domain in response to stiff extracellular matrix signals transduced by the mechanoreceptor Syndecan-4 (SDC4). This phosphorylation generates tension gradients within srGAP2 across the cell (higher tension at leading edge), directing persistent cell migration along stiffness gradients (durotaxis) in triple-negative breast cancer cells. |
srGAP2 tension FRET probe; phosphomimetic/phosphodeficient mutagenesis (Ser206); Transwell invasion assays; xenograft mouse model; membrane protein fractionation; fluorescence imaging |
Theranostics |
Medium |
36593959
|
| 2024 |
SRGAP2A and its human-specific paralogs SRGAP2B/C are expressed in human microglia. SRGAP2B/C are necessary and sufficient (cell-autonomously) to induce neotenic features of microglial structural and functional maturation, and this neoteny non-cell-autonomously impacts synaptic development in cortical pyramidal neurons. |
Xenotransplantation of hiPSC-derived microglia into mouse cortex; mouse genetic models (KD/KO); morphological and functional maturation assays of microglia |
bioRxivpreprint |
Medium |
38979266
|
| 2024 |
SRGAP2A levels at synapses are reduced by SRGAP2B/C, leading to increased postsynaptic accumulation of SYNGAP1. The tempo of synaptogenesis is set by reciprocal antagonism between SRGAP2A and SYNGAP1, and this balance is tipped toward neoteny in human cortical pyramidal neurons by SRGAP2B/C. |
Human cortical pyramidal neurons xenotransplanted into mouse cortex; combinatorial loss-of-function (SRGAP2A, SYNGAP1, SRGAP2B/C); synaptic density and maturation quantification; Western blot for synaptic protein levels |
Neuron |
High |
39406239
|
| 2013 |
srGAP2 inhibits neuronal differentiation and neurite outgrowth through interaction with srGAP3; the isolated F-BAR domain of srGAP2 (but not srGAP1 or srGAP3 F-BAR) can promote VPA-induced neurite initiation. Knockdown of endogenous srGAP2 promotes neurite outgrowth in differentiated cells without facilitating initial neuronal differentiation. |
srGAP2 knockdown and overexpression in mouse Neuro2a cells; RhoGAP-defective mutant expression; GAP-domain point mutants; co-immunoprecipitation of srGAP family interactions |
PloS one |
Medium |
23505444
|