Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein
Open accessAbstract
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a newly described member of the epidermal growth factor (EGF) family that is mitogenic for BALB/c 3T3 cells, inhibits the binding of 125I-EGF to its receptor, and triggers autophosphorylation of the EGF receptor. HB-EGF was purified from the conditioned medium of U-937 cells using cation exchange, copper affinity, heparin affinity, and two rounds of C4 reversed phase liquid chromatography. The elution profile of the first round of C4 column chromatography contained four growth factor activity peaks with similar specific biological activities. N-terminal and tryptic fragment microsequencing demonstrated that these peaks contained different structural forms of the HB-EGF protein. Some of the differences in the various forms of HB-EGF were found to be due to N-terminal heterogeneity. Microsequencing of tryptic fragments indicated that the mature HB-EGF polypeptide can contain at least 86 of the 208 amino acids predicted by nucleotide sequence to be the HB-EGF precursor molecule. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis indicated that the various forms of HB-EGF have apparent molecular masses of 19-23 kDa. Further analysis of the most predominant form of HB-EGF found in U-937 cell conditioned medium indicated that it has a pI of 7.2-7.8 and is O-glycosylated.
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pro-HB-EGF is made as a transmembrane protein and metalloproteinases can cleave it in a juxtamembrane domain to release soluble HB-EGF.
“It is first synthesized as a transmembrane protein (pro-HB-EGF) and can be cleaved by metalloproteinases (MMPs) within a juxtamembrane domain on the cell surface to release soluble HB-EGF (Higashiyama et al., 1991; Higashiyama et al., 1992; Higashiyama and Nanba, 2005).”
From HB-EGF is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration (2012) · cites this paper as Higashiyama et al., 1992
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Intrinsic Disorder and Protein Function
Dunker, A. K., Brown, C. J., Lawson, J. D., Iakoucheva, L. M., & Obradović, Z. (2002) · Biochemistry · doi:10.1021/bi012159+ · Cited by 1,731 · see citing works
HB-EGF is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration
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“It is first synthesized as a transmembrane protein (pro-HB-EGF) and can be cleaved by metalloproteinases (MMPs) within a juxtamembrane domain on the cell surface to release soluble HB-EGF (Higashiyama et al., 1991; Higashiyama et al., 1992; Higashiyama and Nanba, 2005).”
BackgroundADAM-mediated ectodomain shedding of HB-EGF in receptor cross-talk
Higashiyama, S., & Nanba, D. (2005) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2004.11.009 · Cited by 162 · see citing works
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- Authors
- Higashiyama, S., Lau, K., Besner, G. E., Abraham, J. A., & Klagsbrun, M.
- Affiliations
- Harvard University (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1992-03
- Volume
- 267
- Issue
- 9
- Pages
- 6205-6212
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1514034386
- Cited by
- 349
- References
- 30
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 5 · 2023: 2 · 2021: 2 · 2020: 6 · 2019: 5 · 2018: 1 · 2017: 2 · 2016: 5 · 2015: 12 · 2014: 10 · 2013: 8 · 2012: 10
- FWCI
- 12.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01CA045548, CA 37392, CA-45548)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- HB-EGF, epidermal growth factor family, protein structure, O-glycosylation, mitogenic activity, U937 cells, protein purification, primary structure
- MeSH terms
- Amino Acid Sequence, Animals, Antibodies, Biological Assay, Cell Line, Chromatography, Affinity, Chromatography, High Pressure Liquid, DNA Replication, Electrophoresis, Polyacrylamide Gel, Epidermal Growth Factor, Glycosylation, Growth Substances, Heparin, Humans, Isoelectric Focusing, Molecular Sequence Data, Molecular Weight, Peptide Fragments, Peptide Mapping, Platelet-Derived Growth Factor, Sequence Homology, Nucleic Acid, 3T3 Cells, Intercellular Signaling Peptides and Proteins, Mice, Heparin-binding EGF-like Growth Factor
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