Key achievements

The group has been studying the mechanisms and functions of endocytic and autophagic membrane traffic with special emphasis on the roles of Rab5, PI 3-kinase and ubiquitin.

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 Zerial’s 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).