The Simpson-Golabi-Behmel syndrome causative glypican-3, binds to and inhibits the dipeptidyl peptidase activity of CD26.
Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked condition shown to be the result of deletions of the glypican-3 (GPC3) gene. GPC3 is a proteoglycan localized to the cell membrane via a glycosylphosphatidyl-inositol (GPI) anchor. To further elucidate the GPC3 function(s), we have screened various cell lines for proteins that interact with GPC3, resulting in the isolation of a 115 kDa protein, identified as CD26. The interaction occurred with both the glycosylated and unglycosylated forms of GPC3 and led to the inhibition of CD26 peptidase activity. Moreover, introduction of CD26 into Cos-1 cells was accompanied by the up-regulation of cell growth, while inclusion of recombinant GPC3 in the media reduced the growth of CD26 transfected Cos-1 cells, drastically. Furthermore, HepG2 C3A cells containing CD26 underwent apoptosis in the presence of recombinant GPC3 in both concentration and time-dependant manner. In light of the fact that inhibition of CD26 reduces the rate of cell proliferation, we propose that a number of physical findings observed in SGBS patients may be a consequence of a direct interaction of GPC3 with CD26. Furthermore, GPC3 without the GPI anchor is capable of inducing apoptosis indicating that neither the GPI anchor nor the membrane attachment is required for apoptosis induction.
Davoodi
Jamshid
J
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. jdavoodi@ibb.ut.ac.ir
Kelly
John
J
Gendron
Nathalie H
NH
MacKenzie
Alex E
AE
D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D002846:Chromatography, Affinity; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005877:Gigantism / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D053673:Glypicans / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013373:Substance P / Q000378:metabolism; D013577:Syndrome; D014162:Transfection
C105937:GPC3 protein, human; D006023:Glycoproteins; D053673:Glypicans; D011994:Recombinant Proteins; D013373:Substance P; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase