title: Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4.
abstract: An unusual protease gamma-secretase requires functional presenilins and cleaves substrates (e.g. amyloid beta-protein precursor and Notch) with very loose amino acid sequence specificity within the transmembrane region. Here we report that ErbB4, a tyrosine kinase receptor for neuregulins, is a substrate for presenilin-dependent gamma-secretase. Our studies show that constitutive ectodomain shedding of full-length ErbB4 yields the approximately 80-kDa membrane-associated C-terminal fragment (B4-CTF). Subsequent intramembrane cleavage of the B4-CTF was inhibited in the cells devoid of functional presenilins or by treatment of cells with a gamma-secretase inhibitor, leading to enhanced accumulation of B4-CTF. Furthermore, an in vitro gamma-secretase assay demonstrated that the intracellular domain of ErbB4 (B4-ICD) was produced and subsequently released into the soluble fraction in a presenilin-dependent manner. We have also shown that ectopically expressed B4-ICD is localized to the nucleus, suggesting that the presenilin-dependent cleavage of ErbB4 generates the soluble B4-ICD that functions in the nucleus presumably at transcriptional level. Our study indicates that ErbB4 represents a first receptor tyrosine kinase that undergoes intramembrane proteolysis and may mediate a novel signaling function independent of its canonical role as a receptor tyrosine kinase. Our studies also support the idea that presenilins play a generic role in intramembrane cleavage of selected type I membrane proteins.
authors.affiliation: Department of Pathology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Hahn-Jun
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kwang-Mook
authors.initials: KM
authors.lastname: Jung
authors.forename: Yang Z
authors.initials: YZ
authors.lastname: Huang
authors.forename: Lori B
authors.initials: LB
authors.lastname: Bennett
authors.forename: Joanne S
authors.initials: JS
authors.lastname: Lee
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Tae-Wan
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D001483:Base Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D017931:DNA Primers; D010450:Endopeptidases / Q000378:metabolism*; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D021381:Protein Transport; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection
chemical_list: D017931:DNA Primers; D008565:Membrane Proteins; D011994:Recombinant Proteins; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human