Journal
JOURNAL OF CELL SCIENCE
Volume 125, Issue 23, Pages 5860-5872Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.112078
Keywords
Actin; Phactr; RPEL; PP1; Actomyosin
Categories
Funding
- Cancer Research UK
- European Research Council (ERC) [268690]
- EMBO Longterm Fellowship
- ERC [268690]
- European Research Council (ERC) [268690] Funding Source: European Research Council (ERC)
- Cancer Research UK [15687, 15155, 10747] Funding Source: researchfish
Ask authors/readers for more resources
The Phactr family of PP1-binding proteins is implicated in human diseases including Parkinson's, cancer and myocardial infarction. Each Phactr protein contains four G-actin binding RPEL motifs, including an N-terminal motif, abutting a basic element, and a C-terminal triple RPEL repeat, which overlaps a conserved C-terminus required for interaction with PP1. RPEL motifs are also found in the regulatory domains of the MRTF transcriptional coactivators, where they control MRTF subcellular localisation and activity by sensing signal-induced changes in G-actin concentration. However, whether G-actin binding controls Phactr protein function - and its relation to signalling - has not been investigated. Here, we show that Rho-actin signalling induced by serum stimulation promotes the nuclear accumulation of Phactr1, but not other Phactr family members. Actin binding by the three Phactr1 C-terminal RPEL motifs is required for Phactr1 cytoplasmic localisation in resting cells. Phactr1 nuclear accumulation is importin alpha-beta dependent. G-actin and importin alpha-beta bind competitively to nuclear import signals associated with the N- and C-terminal RPEL motifs. All four motifs are required for the inhibition of serum-induced Phactr1 nuclear accumulation when G-actin is elevated. G-actin and PP1 bind competitively to the Phactr1 C-terminal region, and Phactr1 C-terminal RPEL mutants that cannot bind G-actin induce aberrant actomyosin structures dependent on their nuclear accumulation and on PP1 binding. In CHL-1 melanoma cells, Phactr1 exhibits actin-regulated subcellular localisation and is required for stress fibre assembly, motility and invasiveness. These data support a role for Phactr1 in actomyosin assembly and suggest that Phactr1 G-actin sensing allows its coordination with F-actin availability.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available