Journal
JOURNAL OF CELL SCIENCE
Volume 128, Issue 5, Pages 913-922Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.158121
Keywords
Net1; RhoA; Acetylation; Localization; EGF; F-actin
Categories
Funding
- National Cancer Institute [CA116356, CA172129]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RP100502]
- Department of Defense (DOD) Breast Cancer Research Program (BRCP) fellowship [BC112395]
- NATIONAL CANCER INSTITUTE [R01CA116356, R01CA172129] Funding Source: NIH RePORTER
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Net1 isoform A (Net1A) is a RhoA GEF that is required for cell motility and invasion in multiple cancers. Nuclear localization of Net1A negatively regulates its activity, and we have recently shown that Rac1 stimulates Net1A relocalization to the plasma membrane to promote RhoA activation and cytoskeletal reorganization. However, mechanisms controlling the subcellular localization of Net1A are not well understood. Here, we show that Net1A contains two nuclear localization signal (NLS) sequences within its N-terminus and that residues surrounding the second NLS sequence are acetylated. Treatment of cells with deacetylase inhibitors or expression of active Rac1 promotes Net1A acetylation. Deacetylase inhibition is sufficient for Net1A relocalization outside the nucleus, and replacement of the N-terminal acetylation sites with arginine residues prevents cytoplasmic accumulation of Net1A caused by deacetylase inhibition or EGF stimulation. By contrast, replacement of these sites with glutamine residues is sufficient for Net1A relocalization, RhoA activation and downstream signaling. Moreover, the N-terminal acetylation sites are required for rescue of F-actin accumulation and focal adhesion maturation in Net1 knockout MEFs. These data indicate that Net1A acetylation regulates its subcellular localization to impact on RhoA activity and actin cytoskeletal organization.
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