期刊
JOURNAL OF CELL BIOLOGY
卷 211, 期 4, 页码 863-879出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201501072
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资金
- Guy's and St. Thomas' Charity
- Breast Cancer Campaign (London, England, UK)
- Institute of Cancer Research
- Cancer Research UK grant [C309/A8274]
- Experimental Cancer Medicine Centre
- National Institute for Health Research Biomedical Research Centre at Guy's and St. Thomas' National Health Service Foundation Trust
- Department of Health
- National Institute for Health Research comprehensive Biomedical Research Centre
- National Institute for Health Research Biomedical Research Centre at King's College London
- Medical Research Council [1525040] Funding Source: researchfish
P21-activated kinase 4 (PAK4) is a Cdc42 effector protein thought to regulate cell adhesion disassembly in a kinase-dependent manner. We found that PAK4 expression is significantly higher in high-grade human breast cancer patient samples, whereas depletion of PAK4 modifies cell adhesion dynamics of breast cancer cells. Surprisingly, systematic analysis of PAK4 functionality revealed that PAK4-driven adhesion turnover is neither dependent on Cdc42 binding nor kinase activity. Rather, reduced expression of PAK4 leads to a concomitant loss of RhoU expression. We report that RhoU is targeted for ubiquitination by the Rab40A-Cullin 5 complex and demonstrate that PAK4 protects RhoU from ubiquitination in a kinase-independent manner. Overexpression of RhoU rescues the PAK4 depletion phenotype, whereas loss of RhoU expression reduces cell adhesion turnover and migration. These data support a new kinase-independent mechanism for PAK4 function, where an important role of PAK4 in cellular adhesions is to stabilize RhoU protein levels. Thus, PAK4 and RhoU cooperate to drive adhesion turnover and promote cell migration.
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