The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review)

Abstract

Protein phosphorylation is an impo-rtant cellular regulatory mechanism as many enzymes and receptors are activated/deactivated by phosphorylation and dephosphorylation events, by means of kinases and phosph-atases. In particular, the protein kinases are responsible for cellular transduction signaling and their hyperactivity, malfunction or overexpression can be found in several diseases, mostly tumors. Therefore, it is evident that the use of kinase inhibitors can be valuable for the treatment of cancer. In this review, we discuss the mechanism of action of phosphorylation, with particular attention to the importance of phosphorylation under physiological and pathological conditions. We also discuss the possibility of using kinase inhibitors in the treatment of tumors.

Figure 1

Phospho-signaling networks. The mechanism of phosphorylation regulation consists of kinases, phosphatases and their substrates phospho-binding proteins. For example, phosphorylation is activated by stimuli such as epigenetic modifications, cytogenetic alterations, genetic mutations or the tumor micro-environment. Consequently, the protein receives a phosphate group by adenosine triphosphate (ATP) hydrolysis and due to enzymatic activity of kinase. This is the mechanism for the basis of post-translational modification (PTM) formation. In addition, phosphorylation is a reversible process due to activity of phosphatase. Phosphorylation and dephosphorylation are a molecular switch and, in particular, a PTM can cause oncogenic pathway activation by a phospho-binding protein that bind to the phosphate group of a phosphoprotein.

Figure 2

Endothelial growth factor receptor (EGFR) signaling. Ligand binding to the EGFR activates its intrinsic tyrosine kinase activity. The autophosphorylation of EGFR causes the activation of several signaling pathways such as PI3K/AKT and RAS/mitogen-activated protein kinase (MAPK). In both, the phosphorylation is a predominant event and plays an important role in cell survival (AKT activation phosphorylates BAD and MDM2), cell proliferation (AKT activation phosphorylates FoxO, RAS phosphorylates RAF and it phosphorylates MEK that phosphorylates Erk1/2), cell migration (phosphorylation cascade of RAS), apoptosis (AKT phosphorylation is able to activate caspase). However, the phosphorylation of AKT causes mTOR activation, important in protein synthesis.