Type I gamma phosphatidylinositol phosphate kinase modulates adherens junction and E-cadherin trafficking via a direct interaction with mu 1B adaptin.
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 Igamma phosphatidylinositol phosphate kinase (PIPKIgamma) directly binds to E-cadherin and modulates E-cadherin trafficking. PIPKIgamma also interacts with the mu subunits of clathrin adaptor protein (AP) complexes and acts as a signalling scaffold that links AP complexes to E-cadherin. Depletion of PIPKIgamma or disruption of PIPKIgamma 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 PIPKIgamma 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 PIPKIgamma 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.
Ling
Kun
K
Program in Molecular and Cellular Pharmacology, Department of Pharmacology, University of Wisconsin Medical School, Madison, WI 53706, USA.
Bairstow
Shawn F
SF
Carbonara
Chateen
C
Turbin
Dmitry A
DA
Huntsman
David G
DG
Anderson
Richard A
RA
D033983:Adaptor Protein Complex mu Subunits / Q000378:metabolism*; D022005:Adherens Junctions / Q000201:enzymology*; D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002451:Cell Compartmentation / Q000502:physiology; D002460:Cell Line; D004285:Dogs; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007668:Kidney / Q000166:cytology; D008969:Molecular Sequence Data; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology*; D014471:Umbilical Veins / Q000166:cytology
D033983:Adaptor Protein Complex mu Subunits; D015820:Cadherins; D019269:Phosphatidylinositol 4,5-Diphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase