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


Biochemistry & Physiology: Open Access

Author(s): Nickel C, Benzing T, Sellin L, Gerke P, Karihaloo A,

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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-alpha (PKC-alpha), 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.
This article was published in J Clin Invest and referenced in Biochemistry & Physiology: Open Access

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