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Published online January 29, 2007
doi:10.1083/jcb.200606023
The Journal of Cell Biology, Vol. 176, No. 3, 343-353
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Ling et al.
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Article

 Type I{gamma} phosphatidylinositol phosphate kinase modulates adherens junction and E-cadherin trafficking via a direct interaction with µ1B adaptin

Kun Ling1, Shawn F. Bairstow1, Chateen Carbonara1, Dmitry A. Turbin2, David G. Huntsman2, and Richard A. Anderson1

1 Program in Molecular and Cellular Pharmacology, Department of Pharmacology, University of Wisconsin Medical School, Madison, WI 53706
2 Genetic Pathology Evaluation Centre of the Departments of Pathology, British Columbia Cancer Agency, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia V5Z 4E6, Canada

Correspondence to Richard A. Anderson: raanders{at}wisc.edu

Assembly of E-cadherin–based adherens junctions (AJ) is obligatory for establishment of polarized epithelia and plays a key role in repressing the invasiveness of many carcinomas. Here we show that type I{gamma} phosphatidylinositol phosphate kinase (PIPKI{gamma}) directly binds to E-cadherin and modulates E-cadherin trafficking. PIPKI{gamma} also interacts with the µ subunits of clathrin adaptor protein (AP) complexes and acts as a signalling scaffold that links AP complexes to E-cadherin. Depletion of PIPKI{gamma} or disruption of PIPKI{gamma} binding to either E-cadherin or AP complexes results in defects in E-cadherin transport and blocks AJ assembly. An E-cadherin germline mutation that loses PIPKI{gamma} binding and shows disrupted basolateral membrane targeting no longer forms AJs and leads to hereditary gastric cancers. These combined results reveal a novel mechanism where PIPKI{gamma} serves as both a scaffold, which links E-cadherin to AP complexes and the trafficking machinery, and a regulator of trafficking events via the spatial generation of phosphatidylinositol-4,5-bisphosphate.

Abbreviations used in this paper: AJ, adherens junction; AP, clathrin adaptor protein; ECDT, E-cadherin cytoplasmic domain; HEK, human embryonic kidney; HR, heptad repeat; PI4,5P2, phosphatidylinositol-4,5-bisphosphate; PIPKI, type I phosphatidylinositol phosphate kinase; PM, plasma membrane; TfnR, transferrin receptor.


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