Dissecting Major Signaling Pathways throughout the Development of Prostate Cancer

Figure 5

Overview of ERK and PI3K activation and their crosstalk. The binding of the ligand to RTK dimerizes and activates the receptor, leading to the recruitment of multiple Grb2 and Shp2 molecules, which further leads to the binding of a second anchoring protein Gab1 to the complex and to the activation of Son of Sevenless (SOS). This event leads to the activation of Raf/Ras/MEK/ERK pathway. Once phosphorylated, ERKs also phosphorylate a great number of substrates present in both nucleus and cytoplasm. In the nucleus, ERK phosphorylates a series of transcription factors including Elk1, c-Fos, p53, Ets1/2, and c-Jun, each one acting as regulators of cell proliferation, differentiation, and morphogenesis. The recruitment and activation of Grb2 and Shp2 also leads to the recruitment of another docking protein, Gab1. Once phosphorylated, Gab1 recruits PI3K to the membrane, where it phosphorylates the inositol ring of PIP-2 into PIP-3. PIP-3 facilitates the phosphorylation of AKT, which in turn regulates the activity of p53 and BAD. Blue and red arrows indicate up- and downregulated proteins in PCa, respectively.