title: Coronin-1C and RCC2 guide mesenchymal migration by trafficking Rac1 and controlling GEF exposure.
abstract: Sustained forward migration through a fibrillar extracellular matrix requires localization of protrusive signals. Contact with fibronectin at the tip of a cell protrusion activates Rac1, and for linear migration it is necessary to dampen Rac1 activity in off-axial positions and redistribute Rac1 from non-protrusive membrane to the leading edge. Here, we identify interactions between coronin-1C (Coro1C), RCC2 and Rac1 that focus active Rac1 to a single protrusion. Coro1C mediates release of inactive Rac1 from non-protrusive membrane and is necessary for Rac1 redistribution to a protrusive tip and fibronectin-dependent Rac1 activation. The second component, RCC2, attenuates Rac1 activation outside the protrusive tip by binding to the Rac1 switch regions and competitively inhibiting GEF action, thus preventing off-axial protrusion. Depletion of Coro1C or RCC2 by RNA interference causes loss of cell polarity that results in shunting migration in 1D or 3D culture systems. Furthermore, morpholinos against Coro1C or RCC2, or mutation of any of the binding sites in the Rac1-RCC2-Coro1C complex delays the arrival of neural crest derivatives at the correct location in developing zebrafish, demonstrating the crucial role in migration guidance in vivo.
authors: School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors: Rosalind C
authors: RC
authors: Williamson
authors: School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors: Christopher A M
authors: CA
authors: Cowell
authors: School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors: Christina L
authors: CL
authors: Hammond
authors: School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors: Dylan J M
authors: DJ
authors: Bergen
authors: School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors: James A
authors: JA
authors: Roper
authors: School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors: Yi
authors: Y
authors: Feng
authors: Department of Engineering, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors: Thomas C S
authors: TC
authors: Rendall
authors: School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors: Paul R
authors: PR
authors: Race
authors: School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK mark.bass@bristol.ac.uk.
authors: Mark D
authors: MD
authors: Bass
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D015027:Zebrafish; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; C107953:RAC1 protein, human; C477650:RCC2 protein, human; C072061:coronin proteins; D020830:rac1 GTP-Binding Protein
keywords: Coro1C; Coronin-1C; Migration; Neural crest; RCC2; Rac1