Sustained activation of MAPK/ERKs signaling pathway in cystic kidneys from bcl-2 −/− mice

Cell proliferation, survival, and differentiation are carefully orchestrated processes during nephrogenesis that become aberrant during renal cyst formation. Signaling through focal adhesion kinase (FAK) impacts these processes, although its role during nephrogenesis requires further delineation. We previously demonstrated that phosphorylation of FAK and paxillin is not downregulated in cystic kidneys from B cell lymphoma/leukemia-2 (bcl-2) −/− mice. Here we examine whether FAK downstream signaling pathways are affected in these cystic kidneys. Cystic kidneys from bcl-2 −/− mice exhibited sustained phosphorylation of Src and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK, ERK1). However, similar levels of expression were noted for phosphorylated c-Jun NH2-terminal kinase, phosphatidylinositol-3-kinase, and its target protein kinase B/ATP-dependent tyrosine kinase in kidneys from postnatal day 20 bcl-2 +/+ and bcl-2 −/− mice. We also examined expression of the adapter protein Shc, implicated in growth and apoptosis. Expression of p66Shc decreases to low levels in postnatal kidneys, whereas p52/p46Shc was constitutively expressed during nephrogenesis. Shc expression was similar in normal and cystic kidneys. Therefore, sustained activation of MAPK/ERKs through the Src/FAK pathway may contribute to the hyperproliferation observed in cystic kidneys from bcl-2 −/− mice.