Protein phosphatases are enzymes that remove phosphate groups from proteins, a process called dephosphorylation. To understand their function, it is helpful to first consider the opposite process, phosphorylation, where protein kinases add phosphate groups to proteins. This addition and removal of phosphate groups is a widespread method of regulating protein activity within cells. The balance between these two enzyme types determines the functional state of many proteins and controls nearly every cellular process.
The Mechanism of Dephosphorylation
Dephosphorylation is the process by which a protein phosphatase removes a phosphate group from an amino acid residue on a protein. This action is a reversible post-translational modification, a change to the protein that occurs after it has been synthesized. The addition or removal of a phosphate group acts as a molecular switch, altering a protein’s three-dimensional structure and, consequently, its activity. This change in shape can activate or deactivate an enzyme or modify its ability to interact with other proteins.
The chemical mechanism of dephosphorylation involves a hydrolysis reaction, where a water molecule is used to cleave the phosphate group from the protein. This releases the phosphate group as a free ion into the cell. This process regenerates the original hydroxyl group on the amino acid, returning the protein to its previous state. This reversibility allows the cell to reset signaling pathways and respond to new stimuli.
Major Families of Protein Phosphatases
Protein phosphatases are classified into families based on their structure and substrate specificity. The two main superfamilies are the protein tyrosine phosphatases (PTPs) and the serine/threonine phosphatases, named for the amino acid residues they dephosphorylate. Proteins are most commonly phosphorylated on these serine, threonine, and tyrosine residues.
The protein tyrosine phosphatase superfamily specifically dephosphorylates phosphotyrosine residues. PTPs play significant roles in regulating signal transduction pathways, including those initiated by growth factors and hormones. Some PTPs are transmembrane receptors, while others are found within the cytoplasm.
The serine/threonine phosphatases are further divided into two main families: the phosphoprotein phosphatase (PPP) family and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family. The PPP family includes protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). These enzymes are responsible for the majority of serine/threonine dephosphorylation in the cell. The PPM family, which includes PP2C, requires metal ions for its catalytic activity.
Regulation of Key Cellular Functions
One prominent example of phosphatase regulation is the control of the cell cycle, the series of events that lead to cell division. Protein phosphatases, working in concert with protein kinases, ensure that the cell progresses through the different phases of the cycle in an orderly manner. They act at checkpoints to ensure that one phase is completed before the next begins.
Signal transduction, the process by which cells communicate and respond to their environment, is another area heavily reliant on protein phosphatase activity. When a signal, such as a hormone, binds to a receptor on the cell surface, it triggers a cascade of phosphorylation events inside the cell. Protein phosphatases are responsible for terminating these signals and resetting the pathway, allowing the cell to respond to subsequent signals. This ensures that cellular responses are transient and tightly controlled.
Metabolism, the sum of all chemical reactions in the cell, is also regulated by protein phosphatases. Many enzymes involved in metabolic pathways are activated or deactivated by phosphorylation. For instance, the storage and release of glucose are controlled by the phosphorylation state of key enzymes in glycogen metabolism. Protein phosphatases play a part in modulating these pathways in response to the cell’s energy needs.
Implications in Human Disease
Dysfunction in protein phosphatases is implicated in a variety of human diseases. The balance between kinase and phosphatase activity is often disrupted in pathological conditions. This can lead to uncontrolled cell growth, defects in signaling, and metabolic disturbances.
In cancer, some protein phosphatases act as tumor suppressors. They do this by dephosphorylating and inactivating proteins that promote cell proliferation and survival. When these phosphatases are lost or inactivated through mutation or other mechanisms, the pro-growth signaling pathways can become constitutively active, contributing to tumor development. For example, PP2A is considered a tumor suppressor due to its role in dephosphorylating several oncoproteins. Conversely, some phosphatases can be overexpressed in certain cancers and promote tumorigenesis.
Protein phosphatases have also been implicated in neurodegenerative disorders. In Alzheimer’s disease, a pathological hallmark is the accumulation of neurofibrillary tangles, which are primarily composed of the hyperphosphorylated tau protein. Protein phosphatase 2A (PP2A) is the primary phosphatase that dephosphorylates tau in the brain. A decrease in PP2A activity has been observed in Alzheimer’s brains, which is thought to contribute to the abnormal phosphorylation of tau and the subsequent neuronal dysfunction.
Metabolic disorders, such as type 2 diabetes, are also linked to protein phosphatase dysregulation. Insulin signaling is a complex pathway that is tightly regulated by phosphorylation events. Protein-tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin signaling pathway. Elevated levels or activity of PTP1B can dampen the insulin signal, leading to insulin resistance, a key feature of type 2 diabetes. Inhibitors of PTP1B are therefore being investigated as potential therapeutic agents for this disease.