Abstract
The ErbB-4 receptor tyrosine kinase homo- and heterodimerizes following heregulin binding, which provokes increased levels of tyrosine autophosphorylation. Unique to the ErbB family, ErbB-4 is then proteolytically cleaved by α- and γ-secretase to produce an 80 kDa intracellular domain (s80 ICD) fragment. This fragment is found in both the cytoplasm and nucleus of many normal and cancer cells and can interact with transcription factors in the cytoplasm and nucleus. Since the s80 ICD lacks ectodomain sequences known to play a major role in dimerization of ErbB family members, we asked whether the s80 ICD is an active tyrosine kinase. Here, we demonstrate that the s80 ICD is a constitutively active tyrosine kinase and can form homodimers. The s80 ICD is autophosphorylated in cells and can phosphorylate an exogenous substrate in vitro. Also, the s80 ICD can coassociate and dimers are detected by chemical crosslinking. This is the first example of constitutive kinase activation and dimerization totally within the cytoplasmic domain of an ErbB receptor and suggests that the s80 ICD may function to phosphorylate substrates in the cytoplasm or nucleus.
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Acknowledgements
The authors appreciate the efforts of Sue Carpenter in manuscript preparation. We also acknowledge the support of the Department of Defense Grant BC043057 to BL, NIH Grant CA97456 to GC, and both the Vanderbilt Ingram Cancer P30 CA6845 and the Vanderbilt Diabetes Center P30 DK20593 for core resources.
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Linggi, B., Cheng, Q., Rao, A. et al. The ErbB-4 s80 intracellular domain is a constitutively active tyrosine kinase. Oncogene 25, 160–163 (2006). https://doi.org/10.1038/sj.onc.1209003
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DOI: https://doi.org/10.1038/sj.onc.1209003
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