Format

Send to

Choose Destination
J Biol Chem. 2018 Dec 14;293(50):19476-19491. doi: 10.1074/jbc.RA118.001934. Epub 2018 Oct 12.

The mucinous domain of pancreatic carboxyl-ester lipase (CEL) contains core 1/core 2 O-glycans that can be modified by ABO blood group determinants.

Author information

1
From the Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, N-5020 Bergen, Norway.
2
Department of Pathology, Haukeland University Hospital, N-5021 Bergen, Norway.
3
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway.
4
Department of Pediatrics and Adolescent Medicine, Haukeland University Hospital, N-5021 Bergen, Norway.
5
Center for Medical Genetics, Haukeland University Hospital, N-5021 Bergen, Norway.
6
Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
7
Department of Pathology, Ålesund Hospital, N-6017 Ålesund, Norway.
8
Department of Gastrointestinal Surgery, Haukeland University Hospital, N-5021 Bergen, Norway.
9
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, and.
10
INSERM, CRO2, Center for Research in Biological Oncology and Oncopharmacology, Aix-Marseille University, 13284 Marseille Cedex 07, France.
11
From the Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, N-5020 Bergen, Norway, anders.molven@uib.no.

Abstract

Carboxyl-ester lipase (CEL) is a pancreatic fat-digesting enzyme associated with human disease. Rare mutations in the CEL gene cause a syndrome of pancreatic exocrine and endocrine dysfunction denoted MODY8, whereas a recombined CEL allele increases the risk for chronic pancreatitis. Moreover, CEL has been linked to pancreatic ductal adenocarcinoma (PDAC) through a postulated oncofetal CEL variant termed feto-acinar pancreatic protein (FAPP). The monoclonal antibody mAb16D10 was previously reported to detect a glycotope in the highly O-glycosylated, mucin-like C terminus of CEL/FAPP. We here assessed the expression of human CEL in malignant pancreatic lesions and cell lines. CEL was not detectably expressed in neoplastic cells, implying that FAPP is unlikely to be a glycoisoform of CEL in pancreatic cancer. Testing of the mAb16D10 antibody in glycan microarrays then demonstrated that it recognized structures containing terminal GalNAc-α1,3(Fuc-α1,2)Gal (blood group A antigen) and also repeated protein sequences containing GalNAc residues linked to Ser/Thr (Tn antigen), findings that were supported by immunostainings of human pancreatic tissue. To examine whether the CEL glycoprotein might be modified by blood group antigens, we used high-sensitivity MALDI-TOF MS to characterize the released O-glycan pool of CEL immunoprecipitated from human pancreatic juice. We found that the O-glycome of CEL consisted mainly of core 1/core 2 structures with a composition depending on the subject's FUT2 and ABO gene polymorphisms. Thus, among digestive enzymes secreted by the pancreas, CEL is a glycoprotein with some unique characteristics, supporting the view that it could serve additional biological functions to its cholesteryl esterase activity in the duodenum.

KEYWORDS:

ABO blood group; BSDL; CEL; O-glycans; Tn antigen; carboxyl-ester lipase; glycomics; glycoprotein; immunohistochemistry; lipase; pancreas; pancreatic cancer; pathology

PMID:
30315106
PMCID:
PMC6302156
[Available on 2019-12-14]
DOI:
10.1074/jbc.RA118.001934
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center