Ureteric Bud Outgrowth in Response to RET Activation Is Mediated by Phosphatidylinositol 3-Kinase

Autor: Ming Jer Tang, Yang Kao Wang, Si Jie Tsai, Yi Cai, Gregory R. Dressler
Rok vydání: 2002
Předmět:
phosphatidylinositol 3-kinase
Glial Cell Line-Derived Neurotrophic Factor Receptors
cell migration
endocrine system diseases
Nerve Tissue Proteins
Kidney
Transfection
Receptor tyrosine kinase
Cell Line
03 medical and health sciences
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Dogs
Neurotrophic factors
Cell Movement
Proto-Oncogene Proteins
Glial cell line-derived neurotrophic factor
Morphogenesis
Animals
Drosophila Proteins
Glial Cell Line-Derived Neurotrophic Factor
Nerve Growth Factors
chemotaxis
Protein kinase B
Molecular Biology
030304 developmental biology
0303 health sciences
biology
urogenital system
Proto-Oncogene Proteins c-ret
Receptor Protein-Tyrosine Kinases
Cell migration
Cell Biology
GDNF
Cell biology
Ureteric bud
biology.protein
Ureter
RET
GDNF family of ligands
030217 neurology & neurosurgery
Neurotrophin
Signal Transduction
Developmental Biology
Zdroj: Developmental Biology. 243(1):128-136
ISSN: 0012-1606
DOI: 10.1006/dbio.2001.0557
Popis: 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 phosphatidylinositol-linked cell surface protein GFRα1. In the developing kidney, RET, GDNF, and GFRα1 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 chemotaxis 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 chemotaxis 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 morphogenesis.
Databáze: OpenAIRE
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