Figure 3.

Graphic of S1PR pathways involved in RhoA (Ras homolog gene family, member A) and transcription factor activation in glioma cells. A Rho-like subfamily has been identified which becomes activates via the stimulation of G12/13-protein subunit of S1PRs. The guanine nucleotide exchange factor activates downstream signaling intermediates such as Rho GTPases (guanosine triphosphate hydrolase enzymes) namely CDC42 (cell division control protein 42 homolog), RhoA, and Rac1 (Ras-related C3 botulinum toxin substrate 1). An Rho-kinase-dependent increase in the phosphorylation of the myosin light chain (MLC) by inhibiting the myosin-binding subunit (MBS) causes myofibril reorganization, contraction, and activation of downstream transcriptional effectors. The RhoA-mediated (Ras homolog gene family) transcriptional network involves activator protein 1 (AP1), yes-associated protein (YAP), myocardin-related transcription factor A (MRTF-A), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Resulting target genes are involved in the regulation of invasion, proliferation, and differentiation of glioma cells. Inversely, nuclear phosphatase and tensin homolog (PTEN) expression can reduce AKT phosphorylation and consequently inhibit proliferation. On the other hand, Rac1 inhibits migration. Additional abbreviations used in the figure are defined as follows: GEF, guanine nucleotide exchange factor; PKD, protein kinase D; ROCK, RhoA kinase; SRF, serum response factor; ↓inhibition.