期刊
DEVELOPMENTAL BIOLOGY
卷 243, 期 1, 页码 128-136出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1006/dbio.2001.0557
关键词
RET; GDNF; phosphatidylinositol 3-kinase; cell migration; chemotaxis
资金
- NIDDK NIH HHS [DK39255, DK54723] Funding Source: Medline
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P50DK039255, R01DK054723] Funding Source: NIH RePORTER
The c-ret gene encodes a receptor tyrosine kinase (RET) essential for the development of the kidney and enteric nervous system. Activation of RET requires the secreted neurotrophin GDNF (glial cell line-derived neurotrophic factor) and its high affinity receptor, a glycosyl phosphatidylinositot-linked cell surface protein GFRalphal. In the developing kidney, RET, GDNF, and GFRal are all required for directed outgrowth and branching morphogenesis of the ureteric bud epithelium. Using MDCK renal epithelial cells as a model system, activation of RET induces cell migration, scattering, and formation of filopodia and lamellipodia. RET-expressing MDCK cells are able to migrate toward a localized source of GDNF. In this report, the intracellular signaling mechanisms regulating RET-dependent migration and chernotaxis are examined. Activation of RET resulted in increased levels of phosphatidylinositol 3-kinase (PI3K) activity and Akt/PKB phosphorylation. This increase in PI3K activity is essential for regulating the GDNF response, since the specific inhibitor, LY294002, blocks migration and chernotaxis of MDCK cells. Using an in vitro organ culture assay, inhibition of PI3K completely blocks the GDNF-dependent outgrowth of ectopic ureter buds. PI3K is also essential for branching morphogenesis once the ureteric bud has invaded the kidney mesenchyme. The data suggest that activation of RET in the ureteric bud epithelium signals through PI3K to control outgrowth and branching morphogensis. (C) 2002 Elsevier Science (USA).
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