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MBC in Press, published online ahead of print August 29, 2007
Mol. Biol. Cell 10.1091/mbc.E07-03-0223

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Submitted on March 8, 2007
Revised on July 31, 2007
Accepted on August 15, 2007

ErbB4 Isoforms Selectively Regulate Growth Factor–induced MDCK Cell Tubulogenesis

Fenghua Zeng,* Ming-Zhi Zhang,* Amar B. Singh,* Roy Zent,*{dagger} and Raymond C. Harris*{dagger}

*Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, TN 37232; {dagger}Nashville Veterans Affairs Hospital, Nashville, TN, 37232

Monitoring Editor: Keith Mostov

ErbB4, a member of the EGF receptor family that can be activated by heregulin {beta}1 and 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 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-{beta}1 and HB-EGF stimulation; however, compared with HRG-{beta}1, 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. Keywords: renal development, tubulogenesis, MDCK II, ErbB4, HB-EGF.

Address correspondence to: Raymond C. Harris (ray.harris{at}vanderbilt.edu)




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