Unraveling the mechanism behind invasive yeast growth In energy depleted environments, cells will be stimulated to migrate toward nutritional or carbonic sources, and in some cases, may even turn invasive. Why is this so? Many fungi will switch to filamentous growth in order to search for nutrition in energy depleted environments. The filamentous growth is considered invasive, and is associated with Arf3p in yeast, which is the homologue of mammalian Arf6. ADP-ribosylation factors (Arfs) belong to small GTP binding proteins, which can hydrolyze GTP, are critical molecules involved in vesicle transport and actin reorganization. Six isoforms of Arfs were identified in mammalian cells, which can be divided into three classes. Arf class I (Arf1-3) and class II (Arf4-5) primarily regulate vesicular trafficking between the Golgi and endoplasmic reticulum. Class III (Arf6) has been implicated in endocytosis, plasma membrane protein recycling and cytoskeleton remodeling. Arf6 also plays a role in cell adhesion, migration, wound healing, membrane ruffling and metastasis. Similar to other small GTP binding proteins, the activation of Arf is strictly regulated by guanine nucleotide-exchange factors (GEF), which facilitate the dissociation of GDP and its replacement with GTP. All known Arf GEFs are characterized by a central catalytic domain known as the sec7 domain. Aside from invasive growth, Arf3p is also involved in polarity development in yeast. During this process, Arf3p activation is mediated by Yel1p as the GEF; however, further studies revealed that Yel1p is not responsible for the activation of Arf3p on glucose deprivation. The key GEF in this invasive growth is still poorly understood. In July 2015, Professor Lee and Doctor Hsu published their study on the mechanism behind activation of Arf3p in energy depleted environments, in Nature Communications. In this study, a novel GEF “Snf1p”, the homologue of mammalian AMP-activated protein kinase (AMPK), was identified, which is responsible for Arf3p activation in response to glucose depletion. Snf1p is a key metabolic regulator of energy homeostasis and is involved in yeast invasive growth. Snf1p directly binds to and activates Arf3p through the C-terminal regulatory domain. Unlike other GEF for Arfs, Snf1p lacks sec7 domain and is independent of N-terminal Snf1p kinase activity. In conclusion, Arf3p and Snf1p, the homologues of mammalian Arf6 and AMPK respectively, are associated with yeast invasive growth in glucose depleted environments. Recent studies also show that Arf6 and AMPK may be related to migration and invasion in cancer cells. Understanding the regulatory pathway behind may facilitate new drug development in the future. Reference Jia-Wei Hsu, Kuan-Jung Chen and Fang-Jen S. Lee. Snf1/AMPactivated protein kinase activates Arf3p to promote invasive yeast growth via a non-canonical GEF domain. Nat. Commun. 6:7840 DOI:10.1038/ncomms8840 (2015). Professor Fang-Jen Lee Institute of Molecular Medicine fangjen@ntu.edu.tw