Figure 1.

Model of GPCR/β-arr-dependent signal pathways controlling cell survival, cytoskeleton remodeling, and gene expression, leading to enhanced cell growth, invasion and metastasis. In different cancer cells, the binding of ligands to cognate GPCRs leads to the recruitment of β-arrestin (β-arr), which might activate diverse signal-transduction pathways, including Bcl2 and downstream caspase 8. The crosstalk with receptor tyrosine kinases (RTKs), through the recruitment and activation of Src, results in downstream pathway activation, such as members of the Ras/Raf/MEK/ERK family and β-catenin/TCF4. Moreover, GPCR stimulation activates PI3K, leading to AKT/integrin-linked kinase (ILK) signaling and mTOR inhibition. Beyond the cytosolic functions, β-arr might regulate hypoxia-inducible factor 1α (HIF1α) at the levels of transcription, leading to nuclear entry and binding to hypoxia-response elements and the gene transcription. Similarly, β-arr might activate nuclear factor-κB (NF-κB) signaling via inhibition of NF-κB inhibitor (IκB), resulting in the dissociation and subsequent nuclear localization of active NF-κB. At the same time, the interaction of β-arr with actin regulators, such as Filamin-A and LIMK, and ser/thr phosphatases, such as SSH and CIN, leads to enhanced cofilin activity in actin cytoskeleton effects. In addition, GPCR activation might promote the interaction between β-arr and either RHO-guanine nucleotide exchange factors (RHO-GEFs), such as p115RhoGEF or PDZ-RhoGEF, or Rho GTPase-activating proteins (RhoGAPs), such as ARF-GAP21, to activate RhoA GTPase and regulate actin remodeling. β-arr can also bind RalGDS to activate RalA GTPase in cytoskeletal reorganization. Moreover, the interaction of β-arr1 with PDZ-RhoGEF and members of ENA/VASP family, hMENA, might lead to RhoC GTPase activation, causing LIMK-dependent cofilin inhibition and cortactin activation, enhancing invasive behavior. At the same time, β-arr might bind IQGAP1 and RacGAP1, leading to the suppression of Rac1 activity and favoring activation of RhoC and invadopodia functions. The inhibition of β-arr-dependent RASGFR2 activates Rac1 promoting actin polymerization through cofilin activity. β-arr acts as hub regulating several cellular processes related to cancer progression via its interaction with different components of transduction cascades.