ErbB4 isoforms selectively regulate growth factor induced Madin-Darby canine kidney cell tubulogenesis.

Zeng F, Zhang MZ, Singh AB, Zent R, Harris RC
Mol Biol Cell. 2007 18 (11): 4446-56

PMID: 17761534 · PMCID: PMC2043549 · DOI:10.1091/mbc.e07-03-0223

ErbB4, a member of the epidermal growth factor (EGF) receptor family that can be activated by heregulin beta1 and heparin binding (HB)-EGF, is expressed as alternatively spliced isoforms characterized by variant extracellular juxtamembrane (JM) and intracellular cytoplasmic (CYT) domains. ErbB4 plays a critical role in cardiac and neural development. We demonstrated that ErbB4 is expressed in the ureteric buds and developing tubules of embryonic rat kidney and in collecting ducts in adult. The predominant isoforms expressed in kidney are JM-a and CYT-2. In ErbB4-transfected MDCK II cells, basal cell proliferation and hepatocyte growth factor (HGF)-induced tubule formation were decreased by all four isoforms. Only JM-a/CYT-2 cells formed tubules upon HB-EGF stimulation. ErbB4 was activated by both HRG-beta1 and HB-EGF stimulation; however, compared with HRG-beta1, HB-EGF induced phosphorylation of the 80-kDa cytoplasmic cleavage fragment of the JM-a/CYT-2 isoform. HB-EGF also induced early activation of ERK1/2 in JM-a/CYT-2 cells and promoted nuclear translocation of the JM-a/CYT-2 cytoplasmic tail. In summary, our data indicate that JM-a/CYT-2, the ErbB4 isoform that is proteinase cleavable but does not contain a PI3K-binding domain in its cytoplasmic tail, mediates important functions in renal epithelial cells in response to HB-EGF.

MeSH Terms (24)

Active Transport, Cell Nucleus Aging Amino Acid Sequence Animals Cell Adhesion Cell Differentiation Cell Line Cell Proliferation Collagen Type I Dogs ErbB Receptors Gene Expression Regulation Heparin-binding EGF-like Growth Factor Humans Intercellular Signaling Peptides and Proteins Isoenzymes Kidney Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Molecular Sequence Data Neuregulin-1 Phosphorylation Rats Receptor, ErbB-4

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