PYK2, or Proline-rich tyrosine kinase 2, is a protein that plays an important role in various cellular activities. It acts as a signaling molecule, helping cells respond to their surroundings and carry out specific tasks. Understanding PYK2’s functions offers insights into how cells behave and maintain health.
What is PYK2
PYK2 is a non-receptor tyrosine kinase. Kinases are enzymes that add phosphate groups to other proteins, a process called phosphorylation. This addition acts like an “on/off” switch, regulating protein activity and various cellular processes. PYK2 is a 110-kDa protein composed of 1009 amino acids.
PYK2 is closely related to focal adhesion kinase (FAK), sharing a similar structure and the ability to activate downstream signaling pathways. It is primarily a cytoplasmic protein, found in the cell’s main fluid compartment. While it can gather at specific cell contact sites, in neurons, its distribution is more spread out, changing with stimulation. PYK2 is widely present across different tissues, with high concentrations in the central nervous system, epithelial cells, and hematopoietic cells.
PYK2’s Role in Healthy Cells
In healthy cells, PYK2 participates in several physiological processes as a signaling molecule, enabling cells to adapt to their environment. It contributes to cell adhesion, how cells connect and interact with their surroundings. This protein also influences cell migration, the directed movement of cells, and cell proliferation, cell growth and division.
PYK2 also plays a part in immune responses. For instance, it is involved in the migration of macrophages, immune cells, towards areas of inflammation. It also influences bone remodeling, the continuous removal of old bone and formation of new bone. In the nervous system, PYK2 contributes to brain function, including synaptic plasticity (the ability of synapses to strengthen or weaken over time).
PYK2’s Link to Disease
When PYK2’s activity becomes abnormal, it can contribute to the development and progression of various diseases. In cancer, PYK2 is frequently overexpressed and activated in many types, such as breast, lung, liver, prostate, ovarian cancers, gliomas, and multiple myeloma. This overexpression often correlates with poorer patient outcomes. PYK2 promotes cancer cell survival, proliferation, migration, invasion, and resistance to chemotherapy.
PYK2 facilitates tumor growth by activating several oncogenic signaling pathways, such as Wnt/β-catenin, PI3K/Akt, and MAPK/ERK. It can promote metastasis, the spread of cancer cells, by enhancing cell motility and epithelial-mesenchymal transition (EMT), where cells gain migratory properties. For example, in breast cancer, PYK2 is involved in a complex that activates the MAPK signaling pathway, contributing to cell invasion. In lung cancer, elevated PYK2 levels are linked to advanced disease stages and lymph-node metastasis.
PYK2 also plays a role in neurodegenerative disorders, particularly Alzheimer’s disease (AD) and Parkinson’s disease (PD). Genetic variations in the gene encoding PYK2 (PTK2B) have been associated with an increased risk for late-onset Alzheimer’s disease. In AD, PYK2 contributes to amyloid toxicity and tauopathy, hallmarks of the disease. It is implicated in neuronal damage and synaptic dysfunction, mediating negative effects of amyloid-beta oligomers on synaptic function, leading to synapse loss and memory impairment. PYK2 also influences microglial cells, immune cells in the brain, and their secretion of neurotoxic factors in response to amyloid-beta.
PYK2 as a Therapeutic Target
Given its involvement in various diseases, PYK2 is being investigated as a potential target for therapeutic interventions. Scientists consider PYK2 a promising drug target because its activity is directly linked to disease progression, particularly in cancer and neurodegeneration. The aim is to develop PYK2 inhibitors that can block its harmful activity without disrupting its beneficial roles in healthy cells.
Research efforts are focused on creating specific inhibitors that can bind to and deactivate PYK2. These inhibitors could potentially reduce tumor growth, prevent metastasis, and mitigate neuronal damage in neurodegenerative conditions. Developing such drugs presents challenges due to the need for high specificity to avoid off-target effects and potential side effects. Despite these hurdles, ongoing research explores different strategies, including targeting the enzyme’s catalytic domain or interfering with its protein-protein interactions, to create effective PYK2-modulating therapies.