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Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns
D J Riese1, Y Bermingham, T M van Raaij
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA.
Abstract:
Betacellulin is a member of the epidermal growth factor (EGF) family. These soluble proteins are ligands for one or more of the four receptor tyrosine kinases encoded by the erbB gene family (erbB-1/epidermal growth factor receptor (EGFR), neu/erbB-2/HER2, erbB-3/HER3 and erbB-4/HER4). While evidence suggests that betacellulin is a ligand for the EGFR, the ability of betacellulin to regulate other erbB family receptors has not been analysed. Previously we engineered derivatives of the mouse Ba/F3 hematopoietic cell line to ectopically express erbB family receptors, singly and in pairwise combinations. We have stimulated this panel of cell lines with betacellulin and two other EGF family members, EGF itself and neuregulin-beta (NRG-beta). In the cell lines expressing a single erbB family receptor, betacellulin not only stimulated EGFR tyrosine phosphorylation, but it activated erbB-4 as well. Furthermore, in the double recombinant Ba/F3 derivatives, betacellulin stimulated a complex pattern of receptor phosphorylation distinct from the patterns activated by NRG-beta and EGF. Moreover, betacellulin stimulated a complex pattern of interleukin-3 independence in the Ba/F3 derivatives distinct from those activated by NRG-beta and EGF. These data identify a novel receptor for betacellulin and establish that different EGF family ligands activate distinct patterns of receptor phosphorylation and coupling to cellular signaling pathways.
Insights
Betacellulin, an epidermal growth factor (EGF) family member, activates both EGFR and erbB-4 receptors. This study reveals distinct signaling patterns for betacellulin compared to other EGF ligands, uncovering novel receptor interactions.
Area of Science:
- Cellular biology
- Molecular signaling
- Receptor tyrosine kinases
Background:
- Betacellulin belongs to the epidermal growth factor (EGF) family of soluble proteins.
- These proteins act as ligands for receptor tyrosine kinases in the erbB gene family, including EGFR, HER2, HER3, and HER4.
- While betacellulin is known to bind EGFR, its interactions with other erbB family members require further investigation.
Purpose of the Study:
- To investigate the receptor binding and signaling capabilities of betacellulin beyond the epidermal growth factor receptor (EGFR).
- To compare the signaling patterns induced by betacellulin with those of other EGF family members, specifically EGF and neuregulin-beta (NRG-beta).
- To identify novel receptors for betacellulin and elucidate its role in cellular signaling pathways.
Main Methods:
- Engineered Ba/F3 cell lines to express single or paired erbB family receptors.
- Stimulated engineered cell lines with betacellulin, EGF, and neuregulin-beta (NRG-beta).
- Analyzed receptor tyrosine phosphorylation and interleukin-3 independence patterns.
Main Results:
- Betacellulin activated both EGFR and erbB-4 tyrosine phosphorylation in cell lines expressing single erbB receptors.
- Betacellulin induced distinct receptor phosphorylation patterns in double recombinant Ba/F3 cells compared to EGF and NRG-beta.
- Betacellulin triggered unique patterns of interleukin-3 independence, differing from EGF and NRG-beta signaling.
Conclusions:
- Betacellulin interacts with a novel receptor, erbB-4, in addition to EGFR.
- Different EGF family ligands activate distinct receptor phosphorylation and downstream signaling pathways.
- These findings expand the understanding of betacellulin's function and the complexity of erbB receptor signaling.