Journal
JOURNAL OF CELL SCIENCE
Volume 120, Issue 15, Pages 2489-2497Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.03469
Keywords
calcium-sensing receptor; cytoskeleton; beta-arrestin 1; ARF6; ARNO; ELMO
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Funding
- Biotechnology and Biological Sciences Research Council [BB/C515455/1] Funding Source: Medline
- Medical Research Council [G0601810, G0401232, G0601810(80974)] Funding Source: Medline
- Wellcome Trust [059917] Funding Source: Medline
- Biotechnology and Biological Sciences Research Council [BB/C515455/1] Funding Source: researchfish
- Medical Research Council [G0401232] Funding Source: researchfish
- MRC [G0401232] Funding Source: UKRI
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G-protein-coupled receptors (GPCRs) transduce the binding of extracellular stimuli into intracellular signalling cascades that can lead to morphological changes. Here, we demonstrate that stimulation of the calcium-sensing receptor (CaSR), a GPCR that promotes chemotaxis by detecting increases in extracellular calcium, triggers plasma membrane ( PM) ruffling via a pathway that involves beta-arrestin 1, Arf nucleotide binding site opener (ARNO), ADP-ribosylating factor 6 ( ARF6) and engulfment and cell motility protein ( ELMO). Expression of dominant negative beta-arrestin 1 or its knockdown with siRNA impaired the CaSR-induced PM ruffling response. Expression of a catalytically inactive ARNO also reduced CaSR-induced PM ruffling. Furthermore, beta-arrestin 1 co-immunoprecipitated with the CaSR and ARNO under resting conditions. Agonist treatment did not markedly alter beta-arrestin 1 binding to the CaSR or to ARNO but it did elicit the translocation and colocalisation of the CaSR, beta-arrestin 1 and ARNO to membrane protrusions. Furthermore, ARF6 and ELMO, two proteins known to couple ARNO to the cytoskeleton, were required for CaSR-dependent morphological changes and translocated to the PM ruffles. These data suggest that cells ruffle upon CaSR stimulation via a mechanism that involves translocation of beta-arrestin 1 pre-assembled with the CaSR or ARNO, and that ELMO plays an essential role in this CaSR-signalling-induced cytoskeletal reorganisation.
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