Figure 4

Simplified representation of the regulation of actin cytoskeleton pathway and differentially regulated genes. Regulation of actin cytoskeleton encompasses signaling to the cytoskeleton through GPCRs, ITGs and growth factor (GF) – RTKs, leading to diverse cell functions including changes in cell motility, proliferation and survival.^{24, 25, 26, 27} GPCR signaling is activated by a number of external stimuli and signals through heterotrimeric G-proteins, which in turn stimulates a variety of downstream signaling pathways including MAPK, PI3K, FAK and Rho family of GTPases (Rho, Rac and cell division cycle 42 – CDC42) and downstream protein kinase effectors including p21-activated kinase (PAK).^{26, 27} Within the 35-gene signature, F2R and OPN3, both GPCR proteins, were dysregulated. Regulators of G-protein signaling (RGS) are multifunctional signaling proteins that directly bind to activated G-proteins and are integral for modulation of the GPCR signaling process. RGS12, a RGS protein, is upregulated in the resistant cell lines. RTKs are high-affinity cell surface receptors for GF and are key regulators of normal cellular processes and progression of many types of cancers. Predominant signaling pathway that mediates signals from RTK-GF is the MAPK pathway. FAK and PI3K pathways are also known to have important roles in signal transduction. FGF9, a GF, is upregulated in the resistant cell lines. ITGs are a family of cell-surface-adhesion receptors that transmit signals to the cell to determine migration, survival, differentiation and motility in context with the GPCR and RTK-GF signaling. One of the first integrin signaling molecules to be activated is FAK, which in turn activates other signaling pathways. Signaling initiated by GPCR, RTK-GF or ITGs results in remodeling of the actin cytoskeleton and KIF4A, upregulated in resistant cell lines, is a known actin cytoskeleton protein. Genes upregulated in the resistant cell lines are shown in red, whereas downregulated genes are shown in blue