p21-activated kinases in ErbB2-positive breast cancer

Abstract

The activation of receptor tyrosine kinases, particularly ErbB2, has been linked to the genesis and progression of breast cancer. Two of the central signaling pathways activated by ErbB2 are the Ras/Raf-1/Mek/Erk pathway, which plays an important role in tumor cell growth and migration, and the PI3K/Akt pathway, which plays an important role in cell survival. Recently, we and others have shown that signaling through the Ras-Erk pathway can be influenced by p21-activated kinase 1 (Pak1), an effector of the Rho family GTPases Rac and Cdc42. Expression of activated forms of Rac promotes activation of Erk through mechanisms involving Pak1 phosphorylation of Raf-1 and Mek1. In addition, Pak1 has also been implicated in the activation of Akt. However, our understanding regarding the degree to which Rho GTPases, and their effectors such as Pak1, contribute to ErbB2-mediated signaling is very limited.

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Figures and Tables

Figure 1 Dimerization of ErbB2 receptors leads to phosphorylation and activation of several intracellular catalytic substrates, including the Ras/Raf/MEK/Erk, PI3K/Akt and other important signaling pathways that regulate apoptosis, protein synthesis and cellular proliferation. Our experimental results summarized in this Extra View, demonstrate that ErbB2 signaling activates a Rac-Pak signaling pathway that contributes to ErbB2 mediated transformation through the Erk and Akt pathways.

Figure 2 Schematic representation of normal acinar morphology and the effect of ErbB2 signaling on the acinar architecture. Single mammary ephitelial cells seeded on a basement membrane gel recapitulate numerous features of breast epithelium in vivo, including the formation of acinus-like spheroids with a hollow lumen, apicobasal polarization of cells making up these acini and the basal deposition of basement membrane components. Activation of ErbB2 signaling, promotes the activation of several signaling pathways, including the Ras/Raf-1/MEK/Erk and PI3K/Akt pathways disrupting the normal architecture of the acini. Blockade of Rac and Pak activity by using dominant negative mutants as well as small molecule inhibitors restores the normal acinar morphology.

Extra View to: Arias-Romero LE, Villamar-Cruz O, Pacheco A, Kosoff R, Huang M, Muthuswamy SK, Chernoff J. A Rac-Pak signaling pathway is essential for ErbB2-mediated transformation of human breast epithelial cancer cells. Oncogene 2010; 29:5839 - 5849; PMID: 20711231; http://dx.doi.org/10.1038/onc.2010.318

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