Mammalian sterile 20-like kinase 2 (MST2) is a protein kinase enzyme produced from instructions in the STK3 gene. Protein kinases modify other proteins, a process fundamental to cellular communication. As a serine/threonine kinase, MST2’s specific function is to add phosphate groups to target proteins, altering their activity. This role places MST2 within the complex network of interactions that govern cellular behavior.
The Hippo Signaling Pathway
MST2 is a central player in the Hippo signaling pathway, a network that regulates tissue and organ size. It achieves this by balancing cell division with programmed cell death. The Hippo pathway functions as a cascade where one protein activates the next in a specific sequence.
Within this pathway, MST2 works closely with a related protein, MST1. When the Hippo pathway is turned on, MST1 and MST2 become active and function as a unit. Their primary task is to activate the next proteins in the chain, the LATS1 and LATS2 kinases, by modifying them into their active state.
The activation of LATS1/2 by MST1/2 triggers the final steps of the pathway’s core mechanism. The main targets for LATS1/2 are two proteins named YAP and TAZ. Active LATS1/2 phosphorylate YAP and TAZ, which traps them in the cell’s cytoplasm. This prevents YAP and TAZ from moving into the cell’s nucleus, blocking them from turning on genes that stimulate cell growth and proliferation.
Function in Normal Cell Regulation
The activity of the Hippo pathway, driven by MST2, directly influences a cell’s lifecycle. One outcome is the initiation of apoptosis, or programmed cell death. This is an orderly process the body uses to eliminate damaged or unneeded cells. By participating in this cascade, MST2 helps ensure this cellular housekeeping occurs correctly to maintain tissue health.
MST2 also exerts control over the cell cycle, the process a cell undergoes to divide. The pathway’s inhibition of the YAP and TAZ proteins acts as a brake on cell division. This function prevents cells from multiplying when growth is not needed, thereby maintaining a stable number of cells within a tissue.
This regulation is a dynamic system that responds to various cellular cues. For instance, under conditions of cellular stress or DNA damage, the pathway can be activated to halt the cell cycle. If the damage is too severe, it will trigger apoptosis, ensuring faulty cells are repaired or removed.
Implications in Cancer
Due to its role in halting cell growth and promoting cell death, MST2 is classified as a tumor suppressor. Its function is to apply the brakes to cell proliferation. When MST2 is lost or compromised, these brakes are removed. This can happen if the STK3 gene sustains mutations that render it inactive.
Without a functional MST2, the Hippo pathway cannot restrain YAP and TAZ. These proteins become persistently active, driving cells to divide uncontrollably while blocking apoptosis signals. This unchecked proliferation and resistance to cell death are foundational characteristics of cancer.
The loss of MST2 function and disruption of the Hippo pathway have been observed in many human cancers. Studies have linked a dysfunctional Hippo pathway to the development of cancers in the liver, lungs, and colon. In these diseases, the absence of the pathway’s suppressive effects allows cancer cells to thrive, contributing to tumor growth.
Therapeutic Research and Future Directions
Understanding MST2’s role as a tumor suppressor has made the Hippo pathway a focus for cancer research. Scientists are exploring strategies to therapeutically target this network in cancer cells. The goal is to reactivate the pathway’s natural growth-suppressing functions in tumors where it has been silenced.
One approach involves developing small-molecule drugs that could mimic MST2’s function or otherwise restore the pathway’s ability to inhibit YAP and TAZ. By reactivating this cascade, such a therapy could halt the uncontrolled proliferation of cancer cells. This would also make them susceptible to programmed cell death again.
These therapeutic concepts are in various stages of investigation as researchers work to identify effective compounds. The detailed molecular understanding of MST2’s function provides a clear basis for this exploration. This area of study is an active frontier in oncology, aiming to translate basic science discoveries into future clinical applications.