New Routes in GPCR/β-Arrestin-Driven Signaling in Cancer Progression and Metastasis

Abstract

Tumor cells acquire invasive and metastatic behavior by sensing changes in the localization and activation of signaling pathways, which in turn determine changes in actin cytoskeleton. The core-scaffold machinery associated to β-arrestin (β-arr) is a key mechanism of G-protein coupled receptors (GPCR) to achieve spatiotemporal specificity of different signaling complexes driving cancer progression. Within different cellular contexts, the scaffold proteins β-arr1 or β-arr2 may now be considered organizers of protein interaction networks involved in tumor development and metastatic dissemination. Studies have uncovered the importance of the β-arr engagement with a growing number of receptors, signaling molecules, cytoskeleton regulators, epigenetic modifiers, and transcription factors in GPCR-driven tumor promoting pathways. In many of these molecular complexes, β-arrs might provide a physical link to active dynamic cytoskeleton, permitting cancer cells to adapt and modify the tumor microenvironment to promote the metastatic spread. Given the complexity and the multidirectional β-arr-driven signaling in cancer cells, therapeutic targeting of specific GPCR/β-arr molecular mechanisms is an important avenue to explore when considering future new therapeutic options. The focus of this review is to integrate the most recent developments and exciting findings of how highly connected components of β-arr-guided molecular connections to other pathways allow precise control over multiple signaling pathways in tumor progression, revealing ways of therapeutically targeting the convergent signals in patients.

β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4

“…Our data on the impairment in the ability to rearrange the cytoskeleton observed in β-arrestins KO cells indicates that CXCR4-mediated actin polymerization requires the activation of both G-proteins-dependent (47,48), and β-arrestins-dependent pathways. Indeed, β-arrestins by acting as scaffold for several proteins, mediate GPCRs-induced cytoskeleton remodeling (49). Of note, the heterocomplex and CXCL12 alone differently engage the two β-arrestin isoforms.…”

Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

“…Recently, a family of adaptor proteins called β -arrestins has been described as a scaffolding protein for GPCRs to control signal transduction and drive cancer progression, mainly by affecting invasion and metastatic potential of cancer cells via various signaling pathways [ 127 , 128 ]. Mechanistically, β -arrestins control cell migration by inducing the expression and localization of proteins associated with remodeling of the actin cytoskeleton at the leading edge of cells.…”

YAP and endothelin-1 signaling: an emerging alliance in cancer

“…In this landscape, growing evidence discloses how β-arr1 connects the ET A R signaling with other pathways fostering ET A Rintertwined signalings critically involved in the metastatic progression and drug response in many tumor types, including ovarian cancer [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. β-arr1, acting as an adaptor for different signaling molecules distributed in the cytoplasm and in the nucleus, may delineate the fine-tuned duration and localization of the ET-1-guided pathways, driving the formation of multi-protein complex, that prolongs the ET-1 signaling pattern [5,35,44]. Understanding the spatio-temporal control of tumor cell behavior requires information on how signaling complexity is transduced, including the knowledge of the cross-talk with other oncogenic signaling pathways.…”