title: Calmodulin binds HER2 and modulates HER2 signaling.
abstract: Human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of receptor tyrosine kinases, has defined roles in neoplastic transformation and tumor progression. Overexpression of HER2 is an adverse prognostic factor in several human neoplasms and, particularly in breast cancer, correlates strongly with a decrease in overall patient survival. HER2 stimulates breast tumorigenesis by forming protein-protein interactions with a diverse array of intracellular signaling molecules, and evidence suggests that manipulation of these associations holds therapeutic potential. To modulate specific HER2 interactions, the region(s) of HER2 to which each target binds must be accurately identified. Calmodulin (CaM), a ubiquitously expressed Ca(2+) binding protein, interacts with multiple intracellular targets. Interestingly, CaM binds the juxtamembrane region of the epidermal growth factor receptor, a HER2 homolog. Here, we show that CaM interacts, in a Ca(2+)-regulated manner, with two distinct sites on the N-terminal portion of the HER2 intracellular domain. Deletion of residues 676-689 and 714-732 from HER2 prevented CaM-HER2 binding. Inhibition of CaM function or deletion of the CaM binding sites from HER2 significantly decreased both HER2 phosphorylation and HER2-stimulated cell growth. Collectively, these data suggest that inhibition of CaM-HER2 interaction may represent a rational therapeutic strategy for the treatment of patients with breast cancer. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Colin D
authors.initials: CD
authors.lastname: White
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Li
authors.forename: David B
authors.initials: DB
authors.lastname: Sacks
mesh_terms: D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D002118:Calcium; D002147:Calmodulin; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases