TY - JOUR
T1 - Pak1 phosphorylation of Snail, a master regulator of epithelial-to- mesenchyme transition, modulates Snail's subcellular localization and functions
AU - Yang, Zhibo
AU - Rayala, Suresh
AU - Nguyen, Diep
AU - Vadlamudi, Ratna K.
AU - Chen, Shiuan
AU - Kumar, Rakesh
PY - 2005/4/15
Y1 - 2005/4/15
N2 - The process of epithelial-mesenchymal transition plays a pivotal role in the conversion of early stage tumors into invasive malignancies, and has been shown to be regulated by the zinc finger phosphoprotein, Snail; however, no upstream signaling kinases have been shown to modulate Snail functions. Since the invasiveness of breast cancer cells is also influenced by p21-activated kinase 1 (Pak1) signaling, we investigated Pak1's potential mechanistic role in the regulation of Snail functions. We found for the first time that Pak1 promotes transcription repression activity of Snail from E-cadherin, occluclin, and aromatase promoters. Pak1 regulates the repressor activity of Snail by phosphorylating on Ser246. Pak1 phosphorylation of Snail supports Snail's accumulation in the nucleus as well as its repressor functions. A Ser246Ala substitution in Snail or Pak1 knockdown by short interference RNA blocked Pak1-mediated Snail phosphorylation, leading to increased cytoplasmic accumulation of Snail and attenuation of Snail repressor activity in breast cancer cells. The regulation of phosphorylation and function of Snail by Pak1 represents a novel mechanism by which a signaling kinase might contribute to the process of epithelial-mesenchymal transition.
AB - The process of epithelial-mesenchymal transition plays a pivotal role in the conversion of early stage tumors into invasive malignancies, and has been shown to be regulated by the zinc finger phosphoprotein, Snail; however, no upstream signaling kinases have been shown to modulate Snail functions. Since the invasiveness of breast cancer cells is also influenced by p21-activated kinase 1 (Pak1) signaling, we investigated Pak1's potential mechanistic role in the regulation of Snail functions. We found for the first time that Pak1 promotes transcription repression activity of Snail from E-cadherin, occluclin, and aromatase promoters. Pak1 regulates the repressor activity of Snail by phosphorylating on Ser246. Pak1 phosphorylation of Snail supports Snail's accumulation in the nucleus as well as its repressor functions. A Ser246Ala substitution in Snail or Pak1 knockdown by short interference RNA blocked Pak1-mediated Snail phosphorylation, leading to increased cytoplasmic accumulation of Snail and attenuation of Snail repressor activity in breast cancer cells. The regulation of phosphorylation and function of Snail by Pak1 represents a novel mechanism by which a signaling kinase might contribute to the process of epithelial-mesenchymal transition.
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U2 - 10.1158/0008-5472.CAN-04-3480
DO - 10.1158/0008-5472.CAN-04-3480
M3 - Article
C2 - 15833848
AN - SCOPUS:16844377441
SN - 0008-5472
VL - 65
SP - 3179
EP - 3184
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -