title: Destabilization of the epidermal growth factor receptor (EGFR) by a peptide that inhibits EGFR binding to heat shock protein 90 and receptor dimerization.
abstract: An eight-amino acid segment is known to be responsible for the marked difference in the rates of degradation of the EGF receptor (ErbB1) and ErbB2 upon treatment of cells with the Hsp90 inhibitor geldanamycin. We have scrambled the first six amino acids of this segment of the EGF receptor (EGFR), which lies in close association with the ATP binding cleft and the dimerization face. Scrambling these six amino acids markedly reduces EGFR stability, EGF-stimulated receptor dimerization, and autophosphorylation activity. Two peptides were synthesized as follows: one containing the wild-type sequence of the eight-amino acid segment, which we call Disruptin; and one with the scrambled sequence. Disruptin inhibits Hsp90 binding to the EGFR and causes slow degradation of the EGFR in two EGFR-dependent cancer cell lines, whereas the scrambled peptide is inactive. This effect is specific for EGFR versus other Hsp90 client proteins. In the presence of EGF, Disruptin, but not the scrambled peptide, inhibits EGFR dimerization and causes rapid degradation of the EGFR. In contrast to the Hsp90 inhibitor geldanamycin, Disruptin inhibits cancer cell growth by a nonapoptotic mechanism. Disruptin provides proof of concept for the development of a new class of anti-tumor drugs that specifically cause EGFR degradation.
authors.affiliation: From the Departments of Radiation Oncology.
authors.forename: Aarif
authors.initials: A
authors.lastname: Ahsan
authors.forename: Dipankar
authors.initials: D
authors.lastname: Ray
authors.forename: Susmita G
authors.initials: SG
authors.lastname: Ramanand
authors.forename: Ashok
authors.initials: A
authors.lastname: Hegde
authors.forename: Christopher
authors.initials: C
authors.lastname: Whitehead
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Morishima
authors.forename: William B
authors.initials: WB
authors.lastname: Pratt
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Osawa
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Nyati
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D003412:Cricetulus; D019281:Dimerization; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D011485:Protein Binding
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010446:Peptide Fragments; D010455:Peptides; C584969:epidermal growth factor receptor (768-775); D066246:ErbB Receptors; C001277:geldanamycin
keywords: Cancer; EGFR Degradation; Epidermal Growth Factor Receptor (EGFR); Hsp90; Protein Degradation; Receptor Tyrosine Kinase
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