The Role of Arrestins in Development
ABSTRACT β-Arrestins are versatile scaffolding proteins that are involved in orchestrating a large number of signaling cascades. Because β-arrestin 1 and β-arrestin 2 are individually dispensable during development, it has long been assumed that β-arrestins do not play an important role during embryogenesis. Nonetheless, there is growing evidence from both invertebrate and vertebrate animal models that β-arrestins are integral regulators of developmental pathways. They are involved in diverse processes such as early hematopoiesis, establishment of axial development axes, cell convergence and extension movements leading to axial elongation, musculoskeletal and craniofacial development, cell proliferation, and neuronal development. Most of the developmental roles of arrestins involve interactions with or regulation of novel non-G protein-coupled receptor partners, such as atypical seven-transmembrane receptors, small G proteins, and nuclear transcription factors, revealing surprising diversity in arrestin function. In contrast to their largely overlapping roles in G protein-coupled receptor desensitization and internalization, study of the role of arrestins in development has demonstrated marked functional specialization of the β-arrestin 1 and 2 isoforms.
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ABSTRACT: In the developing cerebellum granule cell precursors (GCPs) proliferate in the external granule cell layer before differentiating and migrating to the inner granule cell layer. Aberrant GCP proliferation leads to medulloblastoma, the most prevalent form of childhood brain cancer. Here, we demonstrate that the calcium-sensing receptor (CaSR), a homodimeric G-protein coupled receptor, functions in conjunction with cell adhesion proteins, the integrins, to enhance GCP migration and cell homing by promoting GCP differentiation. During the second postnatal week a robust peak in CaSR expression was observed in GCPs; reciprocal immunoprecipitation experiments conducted during this period established that the CaSR and β1 integrins are present together in a macromolecular protein complex. Analysis of cell-surface proteins demonstrated that activation of the CaSR by positive allosteric modulators promoted plasma membrane expression of β1 integrins via ERK2 and AKT phosphorylation and resulted in increased GCP migration towards an extracellular matrix protein. The results of in vivo experiments whereby CaSR modulators were injected i.c.v. revealed that CaSR activation promoted radial migration of GCPs by enhancing GCP differentiation, and conversely, a CaSR inhibitor disrupted GCP differentiation and promoted GCP proliferation. Our results demonstrate that an ion-sensing G-protein coupled receptor acts to promote neuronal differentiation and homing during cerebellar maturation. These findings together with those of others also suggest that CaSR/integrin complexes act to transduce extracellular calcium signals into cellular movement, and may function in this capacity as a universal cell migration/homing complex in the developing brain. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.Developmental Neurobiology 07/2015; DOI:10.1002/dneu.22321 · 3.37 Impact Factor