Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor.
We recently reported the molecular cloning of HER4/p180erbB4, a new member of the epidermal growth factor receptor family, as well as its activation by a partially purified ligand (Plowman, G. D., Culouscou, J.-M., Whitney, G. S., Green, J. M., Carlton, G. W., Foy, L., Neubauer, M. G., and Shoyab, M. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 1746-1750). In this report we describe the purification to homogeneity of a 45-kDa protein (p45) that induces the differentiation of MDA-MB-453 human breast cancer cells and stimulates the tyrosine phosphorylation of p180erbB4, the HER4-encoded protein. Hydrophobic interaction, ion-exchange, heparin, and size exclusion chromatographies were used to purify this p180erbB4 activator to homogeneity. N-terminal amino acid sequencing suggests that p45 is related to heregulin, a recently reported ligand for p185erbB2. Binding and cross-linking experiments demonstrated that p45 specifically binds to cells expressing recombinant p180erbB4 and not cells expressing recombinant p185erbB2.
Culouscou
J M
JM
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
Plowman
G D
GD
Carlton
G W
GW
Green
J M
JM
Shoyab
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002845:Chromatography; D006224:Cricetinae; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D008969:Molecular Sequence Data; D008970:Molecular Weight; D020880:Neuregulins; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D066247:Receptor, ErbB-4; D011956:Receptors, Cell Surface / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D006023:Glycoproteins; D020880:Neuregulins; D011506:Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D066247:Receptor, ErbB-4