PTEN modulates GDNF/RET mediated chemotaxis and branching morphogenesis in the developing kidney.
The RET receptor tyrosine kinase is activated by GDNF and controls outgrowth and invasion of the ureteric bud epithelia in the developing kidney. In renal epithelial cells and in enteric neuronal precursor cells, activation of RET results in chemotaxis as Ret expressing cells invade the surrounding GDNF expressing tissue. One potential downstream signaling pathway governing RET mediated chemotaxis may require phosphatidylinositol 3-kinase (PI3K), which generates PI(3,4,5) triphosphate. The PTEN tumor suppressor gene encodes a protein and lipid phosphatase that regulates cell growth, apoptosis and many other cellular processes. PTEN helps regulate cellular chemotaxis by antagonizing the PI3K signaling pathway through dephosphorylation of phosphotidylinositol triphosphates. In this report, we show that PTEN suppresses RET mediated cell migration and chemotaxis in cell culture assays, that RET activation results in asymmetric localization of inositol triphosphates and that loss of PTEN affects the pattern of branching morphogenesis in developing mouse kidneys. These data suggest a critical role for the PI3K/PTEN axis in shaping the pattern of epithelial branches in response to RET activation.
Kim
Doyeob
D
Department of Pathology, University of Michigan, MSRB1, BSRB 2049, 109 Zina Pitcher Dr., Ann Arbor, MI 48109, USA.
Dressler
Gregory R
GR
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002633:Chemotaxis; D004285:Dogs; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
D051100:Glial Cell Line-Derived Neurotrophic Factor; D018129:Phosphatidylinositol Phosphates; D011994:Recombinant Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D049452:Green Fluorescent Proteins; D019869:Phosphatidylinositol 3-Kinases; D051096:Proto-Oncogene Proteins c-ret; D051059:PTEN Phosphohydrolase