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The polycystin-1 C-terminal fragment triggers branching morphogenesis and migration of tubular kidney epithelial cells
Christian Nickel, … , Lloyd G. Cantley, Gerd Walz
Christian Nickel, … , Lloyd G. Cantley, Gerd Walz
Published February 15, 2002
Citation Information: J Clin Invest. 2002;109(4):481-489. https://doi.org/10.1172/JCI12867.
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Article

The polycystin-1 C-terminal fragment triggers branching morphogenesis and migration of tubular kidney epithelial cells

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Abstract

Mutations of either PKD1 or PKD2 cause autosomal dominant polycystic kidney disease, a syndrome characterized by extensive formation of renal cysts and progressive renal failure. Homozygous deletion of Pkd1 or Pkd2, the genes encoding polycystin-1 and polycystin-2, disrupt normal renal tubular differentiation in mice but do not affect the early steps of renal development. Here, we show that expression of the C-terminal 112 amino acids of human polycystin-1 triggers branching morphogenesis and migration of inner medullary collecting duct (IMCD) cells, and support in vitro tubule formation. The integrity of the polycystin-2–binding region is necessary but not sufficient to induce branching of IMCD cells. The C-terminal domain of polycystin-1 stimulated protein kinase C-α (PKC-α), but not the extracellular signal–regulated kinases ERK1 or ERK2. Accordingly, inhibition of PKC, but not ERK, prevented polycystin-1–mediated IMCD cell morphogenesis. In contrast, HGF-mediated morphogenesis required ERK activation but was not dependent on PKC. Our findings demonstrate that the C-terminal domain of polycystin-1, acting in a ligand-independent fashion, triggers unique signaling pathways for morphogenesis, and likely plays a central role in polycystin-1 function.

Authors

Christian Nickel, Thomas Benzing, Lorenz Sellin, Peter Gerke, Anil Karihaloo, Zhen-Xiang Liu, Lloyd G. Cantley, Gerd Walz

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Figure 1

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Retroviral gene transfer does not influence branching morphogenesis, mig...
Retroviral gene transfer does not influence branching morphogenesis, migration, or MAP kinase activation of IMCD cells. (a) IMCD cells were transduced with a retrovirus directing the expression of β-galactosidase with a nuclear localization signal (nls-lacZ; right panel). Infected cells (right panel) and untransduced cells (left panel) were stained with X-GAL. Three repeated infections resulted in nearly 100% positive cells, without further selection. (b) Branching morphogenesis of infected IMCD cells. The figure shows phase-contrast microscopy of mock-treated and infected cells. Statistical evaluation demonstrates that retroviral transduction does not alter the branching behavior of IMCD cells (three independent experiments). White bars, basal condition; gray bars, HGF stimulation. (c) Migration of infected IMCD cells. Mock-treated and retrovirally transduced IMCD cells were subjected to cell migration assays as described. Neither basal cell migratory rates nor HGF-stimulated cell migration was altered by stable retroviral transduction in three independent experiments. White bars, basal condition; gray bars, HGF stimulation. (d) MAP kinase activation in infected IMCD cells. After serum starvation, mock-treated and retrovirally transduced IMCD cells were stimulated with solvent or HGF, and harvested. Equal amounts of protein were separated by 12% SDS-PAGE and immunoblotted with antibody against phosphorylated ERK1/2. Retroviral transduction does not activate ERK1 or ERK2 and does not influence HGF-stimulated activation.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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