Regulation of folate receptor internalization by protein kinase C alpha.
The glycosyl-phosphatidylinositol anchored folate receptor (FR) mediates selective delivery of a broad range of experimental drugs to the receptor-rich tumors, but molecular mechanisms controlling FR internalization have not been adequately studied. FR quantitatively recycles between the cell surface and endocytic compartments via a Cdc42-dependent pinocytic pathway. Protein kinase C (PKC) activators including diacylglycerol and phorbol ester have previously been reported to increase the proportion of FR on the cell surface. Here we identify the alpha-subtype of PKC as the mediator of phorbol ester action on FR recycling and provide evidence that activated PKCalpha is recruited to FR-rich membrane microdomains where, in association with its receptor RACK1, it inhibits FR internalization; the activation state of Cdc42 remains unaltered. We also show that the PKC substrate, annexin II, is required for FR internalization. The studies clarify a molecular mechanism for the regulation of FR recycling through PKC which could potentially be exploited for effective drug delivery.
Elnakat
Hala
H
Department of Biochemistry and Cancer Biology, Medical University of Ohio, 3000 Arlington Avenue, Toledo, Ohio 43614, USA.
Gonit
Mesfin
M
Salazar
Marcela D'Alincourt
MD
Zhang
Juan
J
Basrur
Venkatesha
V
Gunning
William
W
Kamen
Barton
B
Ratnam
Manohar
M
D000818:Animals; D017306:Annexin A2 / Q000378:metabolism; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D003902:Detergents / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D008024:Ligands; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D017306:Annexin A2; D002352:Carrier Proteins; D003902:Detergents; D058973:Folate Receptors, GPI-Anchored; D008024:Ligands; D010703:Phorbol Esters; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; C016658:phorbolol myristate acetate; D051571:Protein Kinase C-alpha; D020764:cdc42 GTP-Binding Protein; D013755:Tetradecanoylphorbol Acetate