PTEN regulation of ERK1/2 signaling in cancer.

Since its discovery, the tumor suppressor phosphatase and tensin homolog (PTEN) has become a molecule with a wide spectrum of functions, which is typically meditated through its lipid phosphatase activity; however, PTEN also functions in a phosphatase-independent manner. It is well established that PTEN regulates several signaling pathways, such as phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), janus kinase (JAK)/signal transducers and activators of transcription (STAT), focal adhesion kinase (FAK), and more recent, extracellular signal-regulated kinase (ERK)1/2, where activation of these pathways typically leads to cancer development and progression. In regard to most of these pathways, the underlining molecular mechanism of PTEN-mediated regulation is well established, but not so much for the ERK1/2 pathway. Indeed, accumulating evidence has shown an inverse correlation between PTEN expression and ERK1/2 in several malignancies. However, the detailed mechanism by which PTEN regulates ERK1/2 is poorly understood. In this review, we discuss the role of PTEN in regulating ERK1/2 by directly targeting shc/Raf/MEK and PI3K/AKT cascades, and a putative cross-talk between the two.