PLK1 and β-TrCP-dependent ubiquitination and degradation of Rap1GAP controls cell proliferation

• Published in: PloS one 2014-10, Vol.9 (10), p.e110296-e110296
• Main Authors: Wang, Dejie, Zhang, Pingzhao, Gao, Kun, Tang, Yan, Jin, Xiaofeng, Zhang, Yuanyuan, Yi, Qing, Wang, Chenji, Yu, Long
• Format: Article
• Language: English
• Subjects: beta-Transducin Repeat-Containing Proteins - genetics; beta-Transducin Repeat-Containing Proteins - metabolism; Binding Sites; Biology and Life Sciences; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell growth; Cell Proliferation; Degradation; Gastroenterology; Gene expression; Genetic engineering; GTPase-activating protein; GTPase-Activating Proteins - chemistry; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Guanosine triphosphatases; Guanosine triphosphate; HEK293 Cells; HeLa Cells; Humans; Kinases; Laboratories; Life sciences; Melanoma; Mitosis; Pancreatic cancer; Phosphorylation; Polo-Like Kinase 1; Proteasomes; Protein Binding; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Proteolysis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Rap1 protein; Thyroid gland; Tumor suppressor genes; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0110296

Rap1GAP is a GTPase-activating protein (GAP) that specifically stimulates the GTP hydrolysis of Rap1 GTPase. Although Rap1GAP is recognized as a tumor suppressor gene and downregulated in various cancers, little is known regarding the regulation of Rap1GAP ubiquitination and degradation under physiological conditions. Here, we demonstrated that Rap1GAP is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of Rap1GAP requires the PLK1 kinase and β-TrCP ubiquitin ligase complex. We revealed that PLK1 interacts with Rap1GAP in vivo through recognition of an SSP motif within Rap1GAP. PLK1 phosphorylates Ser525 in conserved 524DSGHVS529 degron of Rap1GAP and promotes its interaction with β-TrCP. We also showed that Rap1GAP was a cell cycle regulator and that tight regulation of the Rap1GAP degradation in mitosis is required for cell proliferation.