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Role played by disabled-2 in albumin induced MAP Kinase signalling

Ramaswamy Diwakar1, Alexander L Pearson, Paul Colville-Nash

  • 1South West Thames Institute for Renal Research, St. Helier Hospital, Wrythe Lane, Carshalton, Surrey SM5 1AA, UK.

Biochemical and Biophysical Research Communications
|December 12, 2007
PubMed

Insights

Disabled-2 (Dab2) regulates kidney cell signaling. While Dab2 typically inhibits the ERK1,2 pathway, this study shows it can also activate it in response to albumin, impacting kidney function.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Signaling

Background:

  • Albumin activates the mitogen-activated protein kinase (MAPK) pathway in kidney proximal tubular cells (PTECs).
  • Megalin, an albumin receptor, has potential signaling properties, but its mechanisms are unclear.
  • The adaptor protein Disabled-2 (Dab2) interacts with megalin and may mediate albumin-induced MAPK signaling.

Purpose of the Study:

  • To investigate the role of Dab2 in albumin-mediated MAPK signaling in PTECs.
  • To examine Dab2's involvement in albumin-induced transforming growth factor-beta 1 (TGF-beta-1) secretion, a MAPK-dependent process.

Main Methods:

  • Utilized RNA interference (RNAi) to knockdown Dab2 protein levels in HKC-8 cells, a model for human PTECs.
  • Assessed the impact of Dab2 knockdown on albumin-induced activation of ERK1,2 and Elk-1.
  • Measured TGF-beta-1 secretion in response to albumin with and without Dab2 knockdown.

Main Results:

  • Albumin activated ERK1,2 and Elk-1 in a MEK-1 dependent manner, leading to TGF-beta-1 secretion.
  • Dab2 knockdown abolished albumin-induced ERK1,2 activation.
  • Dab2 knockdown did not inhibit albumin-induced TGF-beta-1 secretion.
  • Dab2 knockdown showed a trend towards increased pERK1,2 in the absence of albumin, suggesting an inhibitory role.

Conclusions:

  • Dab2 acts as a ligand-dependent, bi-directional regulator of ERK1,2 activity in PTECs.
  • Dab2 can inhibit ERK1,2 activity, but also plays a role in activating ERK1,2 in response to albumin.
  • The role of Dab2 in albumin-induced TGF-beta-1 secretion requires further investigation as it was not inhibited by Dab2 knockdown.

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