期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：148-153
DOI：10.1073/pnas.1412089112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceRab8 is a key regulator of exocytosis. To understand how Rab8 itself is regulated in cells, it is pivotal to study how its guanine nucleotide exchange factor (GEF) Rabin8 is activated. Here we demonstrate that Rabin8 has an autoinhibitory conformation. Phosphorylation of Rabin8 by ERK1/2 in response to EGF relieves the autoinhibition of Rabin8, thus promoting its GEF activity on Rab8. In cells, blocking Rabin8 phosphorylation inhibits vesicular trafficking to the plasma membrane. Our work identifies a molecular mechanism for Rabin8 activation and reveals a regulatory pathway that controls Rab8 activation and vesicular trafficking in response to extracellular signaling. Exocytosis is tightly regulated in many cellular processes, from neurite expansion to tumor proliferation. Rab8, a member of the Rab family of small GTPases, plays an important role in membrane trafficking from the trans-Golgi network and recycling endosomes to the plasma membrane. Rabin8 is a guanine nucleotide exchange factor (GEF) and major activator of Rab8. Investigating how Rabin8 is activated in cells is thus pivotal to the understanding of the regulation of exocytosis. Here we show that phosphorylation serves as an important mechanism for Rabin8 activation. We identified Rabin8 as a direct phospho-substrate of ERK1/2 in response to EGF signaling. At the molecular level, ERK phosphorylation relieves the autoinhibition of Rabin8, thus promoting its GEF activity. We further demonstrate that blocking ERK1/2-mediated phosphorylation of Rabin8 inhibits transferrin recycling to the plasma membrane. Together, our results suggest that ERK1/2 activate Rabin8 to regulate vesicular trafficking to the plasma membrane in response to extracellular signaling.
