Lowe syndrome protein Ocrl1 is translocated to membrane ruffles upon Rac GTPase activation: a new perspective on Lowe syndrome pathophysiology

Abstract

Oculocerebrorenal Lowe syndrome is a rare X-linked disorder characterized by bilateral cataract, mental retardation and renal Fanconi syndrome. The Lowe syndrome protein Ocrl1 is a PIP2 5-phosphatase, primarily localized to the trans-Golgi network (TGN), which 'loss of function' mutations result in PIP2 accumulation in patient's cells. Although PIP2 is involved in many cell functions including signalling, vesicle trafficking and actin polymerization, it has been difficult so far to decipher molecular/cellular mechanisms responsible for Lowe syndrome phenotype. We have recently shown that, through its C-terminal RhoGAP domain, Ocrl1 forms a stable complex with Rac GTPase within the cell. In line with this finding, we report here that upon epidermal growth factor induced Rac activation in COS-7 cells, a fraction of Ocrl1 translocates from TGN to plasma membrane and concentrates in membrane ruffles. In order to investigate the functionality of Ocrl1 in plasma membrane, we have analysed PIP2 distribution in human dermal fibroblasts (HDFs) from Lowe patients versus control HDFs. As revealed by both immunodetection and green fluorescent protein-PH binding, PIP2 was found strikingly to accumulate in PDGF induced ruffles in Lowe HDFs when compared with control. This suggests that Ocrl1 is active as a PIP2 5-phosphatase in Rac induced membrane ruffles. Cellular properties such as cell migration and establishment of cell-cell contacts, which depend on ruffling and lamellipodia formation, should be further investigated to understand the pathophysiology of Lowe syndrome.

A Small Molecule Mimicking a Phosphatidylinositol (4,5)-Bisphosphate Binding Pleckstrin Homology Domain

“…Thus, we tested the compound's potency on three different phosphoinositide phosphatases (SopB, OCRL and SKIP) that preferentially hydrolyze PI(4,5)P 2 (22)(23)(24)(25)(26).…”

Targeting of the type II inositol polyphosphate 5-phosphatase INPP5B to the early secretory pathway

“…This pathway probably links growth factor signalling with membrane dynamics in the endocytic pathway. Like INPP5B, OCRL1 is found in lamellipodia and endosomes, but it is also abundant at the Golgi apparatus Faucherre et al, 2005;Olivos-Glander et al, 1995;Ungewickell et al, 2004). It can interact with RAC1, components of the clathrin coat and both secretory and endosomal RAB proteins Faucherre et al, 2003;Hyvola et al, 2006;Ungewickell et al, 2004).…”

Abnormal bradykinin signalling in fibroblasts deficient in the PIP2 5‐phosphatase, ocrl1

“…The ocrl1 protein is ubiquitously expressed, except for haematopoietic tissues; its localization to the transGolgi network (TGN), endosomes (Choudhury et al 2005;Dressman et al 2000;Ungewickell et al 2004) and the plasma membrane (Erdmann et al 2007;Faucherre et al 2005) suggest that ocrl1 plays a role in protein trafficking. The deficiency of ocrl1 leads to elevated cellular levels of PIP 2 (Wenk et al 2003;Zhang et al 1998).…”