SRC-phosphorylated RAC1/CDC42 guanine nucleotide exchange...

SRC-phosphorylated RAC1/CDC42 guanine nucleotide exchange factors (GEFs), show increased activity in catalyzing formation of RAC1:GTP/CDC42:GTP complexes.

SRC-phosphorylated ELMO1 and DOCK1, components of the bipartite RAC1 GEF DOCK1:ELMO1 (also known as DOCK180:ELMO1), promote RAC1 activation (Makino et al. 2015: human DOCK1 and ELMO1, and chicken SRC, expressed in human embryonic kidney cell line HEK293; Feng et al. 2012: chicken SRC and endogenous DOCK1 and RAC1 proteins in human glioblastoma cell lines were used; Slomiany and Slomiany 2015: endogenous DOCK1, SRC and RAC1 proteins in rat gastric mucosa cells and SRC family inhibitor were used).

SRC phosphorylated RAC1 GEFs TIAM1 and VAV2 activate RAC1 (Servitja et al. 2003: chicken SRC, human TIAM1 and mouse VAV2 expressed in HEK293 cell line; Gonzalez et al. 2006: bovine aortic endothelial cells using endogenous bovine proteins - TIAM1 phosphorylation; Garrett et al. 2008; Ju et al. 2017: human umbilical vein endothelial cells, HUVECs, VAV2 phosphorylation downstream of VEGF treatment; Gianni et al. 2008: human colon adenocarcinoma cell line HT29, endogenous human proteins, VAV2 phosphorylation; Lu et al. 2008: VAV2 phosphorylation in mouse podocytes). SRC-mediated phosphorylation of VAV2 and the subsequent RAC1 activation may require prior SRC-mediated activation of CDC42 by phosphorylation of the CDC42 GEF FARP2 (also known as FERM or FRG) (Kawakatsu et al. 2005: human SRC, mouse VAV2 and RAC1 of unspecified species origin expressed in mouse fibroblast L cells were used; human and mouse RAC1 share 100% sequence identity; Miyamoto et al. 2003: human SRC, FARP2 and CDC42 proteins expressed in HEK293 cells were used).

SRC-phosphorylated RAC1 and CDC42 GEF ARHGEF4 (also known as ASEF) activates RAC1 activation (Itoh et al. 2008: endogenous proteins in human lung adenocarcinoma cell line A431 were used, with ARHGEF4 isoform in the paper corresponding to the splicing isoform 3 in UniProt, which lacks the first 71 amino acids).

When it comes to SRC-mediated phosphorylation of the RAC1 GEF ARHGEF7 (also known as βPix-b), contradictory findings have been reported. SRC was found to phosphorylate ARHGEF7, leading to RAC1 activation (Shin et al. 2019). A subsequent study, however, found that SRC promotes RAC1 activation through ARHGEF7 indirectly, not by phosphorylating ARHGEF7, but by promoting its recruitment to the plasma membrane (Kawase et al. 2022).

RAC1 itself may be a direct phosphorylation target of SRC (Chang et al. 2011).

SRC may also stimulate RAC1 activity indirectly. Namely, SRC has been reported to contribute to activating phosphorylation of STAT3, leading to STAT3-medatied transcription of RAC1 GEF DOCK8 (Wang et al. 2015). SRC-mediated phosphorylation of RAC1 GDP dissociation inhibitors ARHGDIB (also known as RhoGDI2) (Wu et al. 2009) and ARHGDIA (also known as RhoGDI1 or RhoGDI) (DerMardirossian et al. 2006: phosphorylation of human ARHGDIA on Y156 by chicken SRC; Lee et al. 2015) decreases their association with RAC1/CDC42/RHOA, leading to increased RAC1/CDC42/RHOA activity (DerMardirossian et al. 2006, Wu et al. 2009, Lee et al. 2015).