Abstract
β-Arrestins (ARRBs) are ubiquitously expressed scaffold proteins that mediate inactivation of G-protein-coupled receptor signaling, and in certain circumstances, G-protein independent pathways. Intriguingly, the two known ARRBs, β-arrestin1 (ARRB1) and β-Arrestin2 (ARRB2), seem to have opposing functions in regulating signaling cascades in several models in health and disease. Recent evidence suggests that ARRBs are implicated in regulating stem cell maintenance; however, their role, although crucial, is complex, and there is no universal model for ARRB-mediated regulation of stem cell characteristics. For the first time, this review compiles information on the function of ARRBs in stem cell biology and will discuss the role of ARRBs in regulating cell signaling pathways implicated in stem cell maintenance in normal and malignant stem cell populations. Although promising targets for cancer therapy, the ubiquitous nature of ARRBs and the plethora of functions in normal cell biology brings challenges for treatment selectivity. However, recent studies show promising evidence for specifically targeting ARRBs in myeloproliferative neoplasms.
Highlights
Arrestins belong to a family of intracellular proteins that consists of four members
ARRB1 predominantly functions as an oncogene that positively regulates self-renewal in cancer stem cells (CSCs) with the exception of medulloblastoma CSCs where ARRB1 inhibits Sonic Hedgehog (SHH)/Gli signaling and expression of target genes associated with stemness
ARRB2 functions as a negative regulator of stem cell properties in bladder cancer, it induces self-renewal in leukemia where it plays a crucial role in stem cell maintenance
Summary
Arrestins belong to a family of intracellular proteins that consists of four members. Embryonic Stem Cells section, we will review the studies that have confirmed the role of ARRBs in normal stem cell regulaEtmiobnr.yonic stem cells (ESCs) are pluripotent cells that give rise to all somatic cell types in the embryo as it develops [5] Due to their plasticity and potentially unlimited self-renewal capacity, 2E.1S.CEsmabrreyopnriocpSotesmedCfeollrs regenerative medicine and tissue replacement after injury or diseases [6]. A specific siRNA against ARRB2 markedly reduced CXCL12-induced Akt phosphorylation Their results indicated that CXCR7, in cooperation with CXCR4, promotes the survival of HSPCs via the ARRB2-dependent activation of Akt. studies in ARRB1 and ARRB2 knockout mice have shown that depletion of ARRBs does not affect the relative frequency of hematopoietic stem cell (HSC)-enriched cell populations based on the c-Kit+ Lin− Sca-1+ (KLS) expression profile [16]. Depletion of ARRB2 severely impacted HSC functions such as self-renewal and the potential to repopulate mice that were lethally irradiated [16], demonstrating the importance of ARRB2 in regulating pathways implicated in self-renewal
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