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

Christine M Sorenson1, Nader Sheibani

  • 1Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA. cmsorenson@facstaff.wisc.edu

American Journal of Physiology. Renal Physiology
|October 10, 2002
PubMed

Insights

Aberrant kidney development involves focal adhesion kinase (FAK) signaling. In B cell lymphoma/leukemia-2 (bcl-2) knockout mice, sustained MAPK/ERK activation via Src/FAK contributes to renal cyst hyperproliferation.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Signaling

Background:

  • Nephrogenesis involves regulated cell proliferation, survival, and differentiation.
  • Aberrant signaling pathways, including focal adhesion kinase (FAK), are implicated in renal cyst formation.
  • Previous studies showed sustained FAK and paxillin phosphorylation in cystic kidneys of B cell lymphoma/leukemia-2 (bcl-2) knockout mice.

Purpose of the Study:

  • To investigate the downstream signaling pathways affected by FAK in the context of cystic kidneys.
  • To determine the role of FAK-mediated signaling in the hyperproliferation observed in bcl-2 knockout mouse kidneys.

Main Methods:

  • Analysis of protein phosphorylation and expression levels in kidney tissues from postnatal day 20 bcl-2 +/+ and bcl-2 -/- mice.
  • Western blotting was used to assess the activation status of key signaling molecules, including Src, MAPK/ERK, c-Jun NH2-terminal kinase, phosphatidylinositol-3-kinase, protein kinase B, and Shc proteins.

Main Results:

  • Cystic kidneys from bcl-2 -/- mice exhibited sustained phosphorylation of Src and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK).
  • Phosphorylation levels of c-Jun NH2-terminal kinase, phosphatidylinositol-3-kinase, and protein kinase B were similar in normal and cystic kidneys.
  • Expression of Shc adapter proteins (p66Shc, p52/p46Shc) was comparable between normal and cystic kidneys, with p52/p46Shc constitutively expressed during nephrogenesis.

Conclusions:

  • Sustained activation of the MAPK/ERK pathway, potentially through the Src/FAK signaling cascade, may drive the observed hyperproliferation in cystic kidneys of bcl-2 -/- mice.
  • These findings highlight the critical role of FAK-mediated signaling in regulating cell proliferation during kidney development and disease.

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