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

ABSTRACT: 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.

SUBMITTER: Zeng F

PROVIDER: S-EPMC2043549 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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

Zeng Fenghua F Zhang Ming-Zhi MZ Singh Amar B AB Zent Roy R Harris Raymond C RC

Molecular biology of the cell 20070829 11

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 p ...[more]

PMID: 17761534

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Project description:Madin-Darby canine kidney (MDCK) cells were cultured on polycarbonate filters to study the synthesis and sorting of proteoglycans in polarized epithelial cells. Two strains of MDCK cells were used. MDCK I cells resemble distal tubule epithelial cells, and MDCK II cells share some characteristics with proximal tubule cells. Both strains were grown to confluency and labelled with [35S]sulphate for 24 h. The apical and basolateral media and the cell fractions were harvested and analysed by DEAE ion-exchange chromatography. A large portion of the [35S]sulphate-labelled macromolecules bound strongly to the ion-exchange columns, and could be eluted in three distinct peaks. The latest eluting peak was demonstrated to contain almost exclusively chondroitin sulphate, whereas peak 2 contained mostly heparan sulphate, demonstrated by using chondroitinase ABC and nitrous acid (pH 1.5) respectively to depolymerize the [35S]glycosaminoglycan chains. Peak 1 contained negligible amounts of proteoglycans. Large differences could be observed in proteoglycan sorting in MDCK I and II cells. Strain I secreted approx. 67% of the proteoglycans to the apical side and 17% to the basolateral side. The cell fraction contained 17% of the proteoglycans after 24 h of labelling. In contrast, 19% of the proteoglycans were sorted to the apical side of MDCK II cells and 61% to the basolateral side, whereas the cell fraction contained 20%. Furthermore, the level of [35S]proteoglycan biosynthesis (apical and basolateral media and cell fraction total) was higher in MDCK I cells than in strain II. Based on the amount of material degraded by chondroitinase ABC and nitrous acid respectively, and the total amounts of [35S]proteoglycans recovered from the cells, it was calculated that the MDCK I strain synthesized approx. 56% chondroitin sulphate and 44% heparan sulphate. In contrast, the MDCK II strain synthesized 69% heparan sulphate and 31% chondroitin sulphate. To further identify the [35S]proteoglycans synthesized by MDCK I and II cells, antibodies against perlecan, versican and syndecan were used. The antibody against mouse syndecan did not cross-react with any of the proteoglycans produced in MDCK I or II cells. Both MDCK I and II cells expressed perlecan; 57-61% could be recovered from the basolateral fractions and 18-34% from the apical medium. Versican was also found in both MDCK I and II cells. Compared with perlecan, a larger percentage of versican (43-53%) was found in the cell fractions.

Dataset Information

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

Publications

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

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