Phosphoinositide Metabolism
Growing evidence implicates membrane lipids, in particular phosphoinositides,
in the regulation of clathrin-mediated endocytosis. Several endocytotic proteins
such as the and subunits of heterotetrameric AP-2 complexes (Gaidarov and Keen,
1999; Collins et al., 2002; Rohde et al., 2002; fig. 1)), the A/ENTH domains of AP180
and epsin and the pleckstrin homology (PH) domain of the large GTPase dynamin can interact
directly with PI(4,5)P2.
Figure 1: 3D-structure of the PIP2/ IP6 binding site within the AP-2mu subunit
obtained by X-ray crystallography (Collins et al., 2002); courtesy of
Dr. David Owen, Cambridge, UK)
The importance of this lipid is evidenced by the fact that depletion of leads to
mislocalization of plasmalemmal clathrin and AP-2 and complete inhibition of clathrin-dependent
receptor internalization (fig. 2).
Figure 2: Depletion of PIP2 leads to mislocalization of AP-2 (bottom) and impaired internalization
of plasmalemmal receptors (top); Krauss et al., 2003)
PIP kinase type I (PIPKIγ and synaptojanin 1, the major brain PI(4)phosphate 5-kinase and
PI(4,5)P2 polyphosphoinositide phosphatase, respectively, are concentrated at synapses. PIPKIγ
is activated by the small GTPase Arf6 (Krauss et al., 2003) and the integrin-actin-linking
focal adhesion protein talin, both of which are also concentrated at synapses.
. We have identified other novel regulators of PIPKIγ and are also investigating how PI(
4,5)P2 metabolism is regulated during synaptic
activity and how retrograde messengers may affect phosphoinositide metabolism.
To investigate the putative role of PI(4,5)P2 in regulated exocytosis we are collaborating
with the labs of Drs. Erwin Neher and Reinhard Jahn (MPI, Göttingen).
Last update: Nov, 2005 by Claus Rodemer
