title: The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells.
abstract: ERBB4/HER4 (referred to here as ERBB4) is a unique member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. In contrast to the other three members of the EGFR family (i.e., EGFR, ERBB2/HER2/NEU, and ERBB3), which are associated with aggressive forms of human cancers, ERBB4 expression seems to be selectively lost in tumors with aggressive phenotypes. Consistent with this observation, we show that ERBB4 induces apoptosis when reintroduced into breast cancer cell lines or when endogenous ERBB4 is activated by a ligand. We further show that ligand activation and subsequent proteolytic processing of endogenous ERBB4 results in mitochondrial accumulation of the ERBB4 intracellular domain (4ICD) and cytochrome c efflux, the essential and committed step of mitochondrial regulated apoptosis. Our results indicate that 4ICD is functionally similar to BH3-only proteins, proapoptotic members of the BCL-2 family required for initiation of mitochondrial dysfunction through activation of the proapoptotic multi-BH domain proteins BAX/BAK. Similar to other BH3-only proteins, 4ICD cell-killing activity requires an intact BH3 domain and 4ICD interaction with the antiapoptotic protein BCL-2, suppressed 4ICD-induced apoptosis. Unique among BH3-only proteins, however, is the essential requirement of BAK but not BAX to transmit the 4ICD apoptotic signal. Clinically, cytosolic but not membrane ERBB4/4ICD expression in primary human breast tumors was associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression. Thus, we propose that ligand-induced mitochondrial accumulation of 4ICD represents a unique mechanism of action for transmembrane receptors, directly coupling a cell surface signal to the tumor cell mitochondrial apoptotic pathway.
authors.affiliation: Department of Biochemistry, Tulane University Health Sciences Center, Tulane Cancer Center, LA 70112-2699, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Naresh
authors.forename: Weiwen
authors.initials: W
authors.lastname: Long
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Vidal
authors.forename: William C
authors.initials: WC
authors.lastname: Wimley
authors.forename: Luis
authors.initials: L
authors.lastname: Marrero
authors.forename: Carolyn I
authors.initials: CI
authors.lastname: Sartor
authors.forename: Sian
authors.initials: S
authors.lastname: Tovey
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Cooke
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
authors.forename: Frank E
authors.initials: FE
authors.lastname: Jones
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020890:Neuregulin-1 / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D066247:Receptor, ErbB-4; D017386:Sequence Homology, Amino Acid; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: C494772:BAK1 protein, human; C474007:Bax protein (53-86); D020890:Neuregulin-1; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; C087230:heregulin beta1; D045304:Cytochromes c; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4