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P21-activated kinase-1 phosphorylates and transactivates estrogen receptor-alpha and promotes hyperplasia in mammary

Rui-An Wang1, Abhijit Mazumdar, Ratna K Vadlamudi

  • 1Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4009, USA.

The EMBO Journal
|October 11, 2002
PubMed

Insights

p21-activated kinase-1 (Pak1) promotes mammary gland hyperplasia by activating the estrogen receptor-alpha (ER). Pak1 directly phosphorylates ER, enhancing its transactivation functions and leading to epithelial overgrowth.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • p21-activated kinase-1 (Pak1) is implicated in cytoskeleton organization and signaling in cancer cells.
  • Estrogen receptor-alpha (ER) is a key regulator of mammary gland development and function.

Purpose of the Study:

  • To investigate the role of Pak1 in mammary gland development and ER signaling.
  • To elucidate the molecular mechanisms by which Pak1 influences ER activity.

Main Methods:

  • Inhibition of Pak1 using dominant-negative fragments and short interference RNA.
  • Development of a transgenic murine model with constitutively active Pak1.
  • Analysis of mammary gland morphology, ER transactivation, and downstream gene expression.
  • Site-directed mutagenesis to study Pak1 phosphorylation of ER at Ser305.

Main Results:

  • Pak1 inhibition reduced ER transactivation functions.
  • Constitutively active Pak1 in murine mammary glands led to hyperplasia, apocrine metaplasia, and hyperdevelopment.
  • Active Pak1 increased mitogen-activated protein kinase activation and ER target gene expression.
  • Pak1 directly phosphorylated ER at Ser305, a modification crucial for ER transactivation.

Conclusions:

  • Pak1 plays a significant role in mammary gland hyperplasia.
  • The Pak1-ER signaling pathway is a novel mechanism regulating mammary epithelial proliferation.
  • Pak1-mediated phosphorylation of ER at Ser305 is a key event in promoting ER activity and mammary gland overgrowth.

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