It is no coincidence that one cellular process is mentioned time and time again in discussions of cell-signaling pathways in cancer. Since its discovery, phosphorylation has come to be recognized as a global regulator of cellular activity, and abnormal phosphorylation is implicated in a host of human diseases.
In this report, we probe a little deeper to understand what exactly protein phosphorylation does; why it is such a vital, ubiquitous process; and how it continues to further our understanding of diseases such as cancer.
A Minor Modification With a Major Role
Once a gene is expressed and translated into a functional cellular protein, the cell is able to control the protein’s fate through the use of posttranslational modifications (PTMs). Phosphorylation is the most important and most thoroughly researched form of PTM.
Phosphorylation of a protein involves the enzymatically mediated addition of a phosphate group (PO4) to its amino acid side chains. Phosphorylated proteins were observed as far back as the early 1900s, but it was not until the 1950s that the pioneering, and ultimately Nobel Prizewinning, discoveries of Edmond H. Fischer and Edwin G. Krebs determined that phosphorylation was a reversible, enzymatically mediated process, capable of modifying the function of a protein.
Today, it is believed that as many as one-third of all proteins in the cell are phosphorylated at one time or another, and half of these proteins likely harbor more than 1 phosphorylation site, with different sites often eliciting quite different cellular responses.
Phosphorylation and the reverse reaction, dephosphorylation, occur thanks to the actions of 2 key enzymes. Protein kinases phosphorylate proteins by transferring a phosphate group from adenosine triphosphate (ATP) to their target protein. This process is balanced by the action of protein phosphatases, which can subsequently remove the phosphate group. The amount of phosphate that is associated with a protein is therefore precisely determined by the relative activities of the associated kinase and phosphatase. As much as 2% to 5% of the human genome is thought to encode protein kinases and phosphatases.
The most common amino acids to be phosphorylated on eukaryotic proteins (proteins found in all organisms except bacteria) are serine, threonine, and tyrosine.
Functions of Phosphorylation Are Varied
At the level of a single protein, the binding of a negatively charged phosphate group can lead to changes in the structure of a protein, which alter the way that it functions. If the targeted protein is an enzyme, phosphorylation and dephosphorylation can impact its enzymatic activity, essentially acting like a switch, turning it on and off in a regulated manner.
Another outcome of structural changes to the phosphorylated protein is the facilitation of binding to a partner protein. In this way, phosphorylation can regulate protein-protein interactions. The phosphorylation of a protein can also target it for degradation and removal from the cell by the ubiquitin-proteasome system.
Protein phosphorylation also has a vital role in intracellular signal transduction. Many of the proteins that make up a signaling pathway are kinases, from the tyrosine kinase receptors at the cell surface to downstream effector proteins, many of which are serine/threonine kinases.
In a nutshell, ligand binding at the cell surface establishes a phosphorylation cascade, with the phosphorylation and activation of 1 protein stimulating the phosphorylation of another, subsequently amplifying a signal and transmitting it through the cell. The signal continues to propagate until it is switched off by the action of a phosphatase.
In addition to proteins, other kinds of molecules can also be phosphorylated. In particular, the phosphorylation of phosphoinositide lipids, such as phosphatidylinositol-4,5-bisphosphate (PIP2), at various positions on their inositol ring, also plays a key role in signal transduction.
Defining the Role of Phosphorylation in Cancer
Phosphorylation plays a vital role in regulating many intracellular processes such as growth, proliferation, and cell division. Thus, any perturbations in the phosphorylation process are likely to drive many of the hallmarks of cancer, such as unchecked cell growth and proliferation. Indeed, mutations in kinases and phosphatases are frequently implicated in a number of different cancers, and many of the genes encoding for these proteins are oncogenes or tumor suppressors.
Overexpression or mutations that lead to constitutive activation of phosphorylation machinery will inevitably disrupt its delicate balance in the cell, driving the inappropriate activation or deactivation of the cellular processes it controls.