Key Achievements
The group has been studying the mechanisms that control cellular membrane dynamics and how their dysregulation may cause cancer. Main focus has been on membrane dynamics during endocytic and autophagic membrane traffic as well as cell division (https://en.wikipedia.org/wiki/Cell_division).
The following findings have been of special importance:
Identification of Rabaptin-5 as the first effector of the small GTPase Rab5 in endosome fusion (Cell, 1995)
Identification of the conserved FYVE zinc finger, and demonstration that a FYVE finger mediates the endosomal localization of the early-endosomal autoantigen EEA1 (J.Biol.Chem.,1996)
Demonstration that the FYVE finger binds specifically to the PI 3-kinase product, phosphatidylinositol 3-phosphate (PI3P) (Nature, 1998a)
Identification of EEA1 as an effector of Rab5 and PI3P in endosome fusion (Nature, 1998b).
Construction of a tandem FYVE domain (2xFYVE) as a probe for PI3P and demonstration that PI3P is specifically localized to endosomes (EMBO J., 2000).
Demonstration that hepatocyte growth factor regulated tyrosine kinase substrate, Hrs, is recruited to endosomes by binding PI3P (J. Cell Sci., 2001).
Discovery that Hrs binds to clathrin via a C-terminal clathrin-box motif and recruits clathrin to endosomes (EMBO J., 2001)
Demonstration that Hrs binds ubiquitin via a ubiquitin-interacting motif (UIM) and recruits ubiquitinated membrane proteins into clathrin-coated microdomains on endosomes for their targeting to lysosomes (Nat. Cell Biol., 2002).
Discovery that Hrs recruits endosomal sorting complex required for transport (ESCRT)-I to endosome membranes (J. Cell Biol., 2003).
Identification of hepatocellular carcinoma related protein 1 (HCRP1) as a subunit of mammalian ESCRT-I, suggesting a new possible link between ESCRT-I and tumour suppression (Mol. Biol. Cell,2004).
Discovery that the steroid hormone ecdysone induces developmental autophagy in Drosophila through downregulating the class I PI 3-kinase pathway (Dev. Cell, 2004).
In collaboration with Marino Zerials lab, identification of KIF-16B as a kinesin motor protein that binds PI3P and powers the motility of PI3P-containing endosomes in the plus direction along microtubules (Cell,2005).
Discovery of the GLUE domain as a ubiquitin-and phosphoinositide-binding domain present in the mammalian ESCRT-II subunit Eap45/Vps36 (J. Biol. Chem., 2005), and determination of the structure of the GLUE domain complexed with ubiquitin (Nat. Struct. Mol. Biol., 2006a) (collaboration with Soichi Wakatsuki's lab).
Demonstration that the PI3P 5-kinase Fab1 is essential for viability and negative growth control in Drosophila, and that this kinase regulates late-endosomal trafficking but not Wnt, Notch and Dpp signalling (Mol. Biol. Cell, 2006).
Demonstration that clathrin sequesters Hrs into restricted microdomains of endosome membranes, and that this is important for the function of Hrs in endosomal protein sorting (J. Cell Sci., 2006).
In collaboration with Soichi Wakatsuki’s lab, determination of the crystal structure of Hrs-UIM in complex with ubiquitin,and demonstration that the UIM binds two ubiquitin molecules, which is important for its function in endosomal protein sorting (Nat. Struct. Mol.Biol., 2006b).
Identification of the cytokine-independent survival kinase, CISK, as a key factor in regulating stability of the chemokine receptor CXCR4 downstream of PI 3-kinase. (EMBO J., 2006).
Demonstration that ESCRTs mediate autophagic degradation, and that this is required for clearance of toxic protein aggregates, thereby having a neuroprotective function (Curr.Biol, 2007; J. Cell Biol., 2007).
Identification of Eps15b as an Eps15-related protein on early endosomes that interacts with Hrs to mediate degradation of epidermal growth factor receptors (J. Cell Biol., 2008).
Demonstration that the “autophagy receptor” p62 is required for the formation of protein aggregates in the brain of adult fruit flies (J. Cell Biol. 2008). (http://jcb.rupress.org/content/180/6/1065.long)
Demonstration that PI3P controls cytokinesis through KIF13A-mediated recruitment of the PI3P-binding protein FYVE-CENT to the midbody (Nature Cell Biol. 2010). (http://www.nature.com/articles/ncb2036)
Demonstration that the fruit fly homologue of CIN85, Cindr, interacts with anillin to control cytokinesis in flies (Curr.Biol. 2010). (http://www.sciencedirect.com/science/article/pii/S0960982210004446?via%3Dihub)
Demonstration that ESCRT-mediated lysosomal degradation of the ubiquitinated fibronectin receptor, a5b1 integrin, controls fibroblast migration (Dev.Cell 2010). (http://www.sciencedirect.com/journal/developmental-cell)
Identification of a mechanistic link between selective autophagy and cell death during late oogenesis in fruit flies (J. Cell Biol. 2010). (http://jcb.rupress.org/content/190/4/523.long)
Demonstration that the PI3P-binding protein ANCHR mediates Aurora B-dependent abscission checkpoint control in cytokinesis via binding to the ESCRT regulator VPS4 (Nature Cell Biol. 2014). (http://www.nature.com/articles/ncb2959)
Demonstration that two PI3P-binding proteins, Protrudin and FYCO1, cooperate to mediate endosome exocytosis and cellular protrusions via formation of ER-endosome contact sites (Nature 2015a). (http://www.nature.com/articles/nature14359)
Demonstration that ESCRT-III mediates sealing of the reforming nuclear envelope during mitotic exit, and recruit the microtubule-severing ATPase Spastin to coordinate sealing with mitotic spindle disassembly (Nature 2015b). (http://www.nature.com/articles/nature14408)
Demonstration that Alix and ESCRT-I and –II function as parallel ESCRT-III recruiters during cytokinetic abscission (J. Cell Biol. 2016). (http://jcb.rupress.org/content/212/5/499.long )
Demonstration that PI3P controls mTORC1 signalling through lysosomal positioning, mediated by the PI3P-binding proteins Protrudin and FYCO1 (J.Cell Biol. 2017). (http://jcb.rupress.org/content/216/12/4217.long)