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

Fenghua Zeng, Ming Zhi Zhang, Amar B. Singh, Roy Zent, Raymond C. Harris

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


ErbB4, a member of the epidermal growth factor (EGF) receptor family that can be activated by heregulin β1 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-β1 and HB-EGF stimulation; however, compared with HRG-β1, 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.

Original languageEnglish (US)
Pages (from-to)4446-4456
Number of pages11
JournalMolecular biology of the cell
Issue number11
StatePublished - Nov 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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