Description
Thymosin ß4 (TB4) is a “moonlighting protein” 1 . Simply put it is multi-functional. While that may seem to be a concept that is simple to grasp, after-all multi-functional simply means it does a bunch of different things, in reality, in the context of biology to label a peptide a “moonlighting protein” adds complexity to our understanding of when, how and to what extent that peptide act. As an analogy, in our world a fork residing in the hand of the hungry will function as a tool for getting food into mouth. Remove that fork from the kitchen and put it in the hand of someone in a life threatening situation and it becomes a weapon. Whether that fork-weapon is used to inflict damage or defend against it depends on the tissue that holds it. In other words the multi-fuction of the fork never depends on the fork itself. The function always depends on where it resides and the hand that holds it, be it a hungry hand, angry hand or a scared hand.
If we move into the world of the cell and look at the concept of moonlighting proteins we’ll bump into one such protein called phosphoglucose isomerase. Most texts will tell you that phosphoglucose isomerase is the enzyme responsible for the second step of glycolysis (degradation of glucose into pyruvate) and is involved in glucogenesis (formation of glucose through the breakdown of glycogen). However the proper way to understand it or rather the moonlighting way is to understand that it’s behavior is permissive not absolute. Phosphoglucose isomerase is a protein that can be a key enzyme in glycolysis but when found moonlighting outside the cell may act as a nerve growth factor.
How a moonlightling protein functions will depend on cellular localization (i.e. where within the cell does it find itself), cell type, oligomeric state (the folding or 3 dimensional protein shape), or the cellular concentration of a ligand, substrate or cofactor (often a threshold amount need be present to trigger action). We are already familiar with these concepts. For example let’s take a quick look at the the oligomeric state (i.e. tertiary structure) as it relates to autocrine Growth Hormone/IGF-1. As you know there exists growth hormone of the type that is released from cells within the pituitary, which flows to the GH-receptors on cells in the liver where it binds and one of the results of this binding is the eventual making and release of IGF-1 which itself flows to tissue where it finds a receptor to bind to. This sort of activity is endocrine or systemic activity.
Now autocrine or local activity in the realm of GH/IGF-1 is where we come in contact with the concept of oligomeric state. Cells everywhere in the body posses various abilities to make a little bit of factors for use therein or use in a way that also affects neighboring cells. In regard to GH, non-liver cells do this by binding a GH molecule to a GH-receptor inside the cell and then birthing the two together. Birthing means they are taken to the cell membrane where the GH/receptor complex is pushed up through the cell membrane. Now the shape of the GH/receptor while it is still inside the cell is turned off. It is off because it’s 3 dimensional shape is not yet the native active state. It is like a closed umbrella and only when it makes it’s way to the cell surface dose the shape become native, active and functional like an open umbrella. The 3 dimensional state of a protein is something that shouldn’t be foreign to readers of this forum.
On the off chance that this concept of muscle cells birthing their own growth factor/receptor is new to you I will add that GH or IGF-1 that is released from the liver or from an exogenous adminstration will not be able to bind to these occupied GH/receptor complexes birthed as autocrine factors. I will also add, welcome to my board. 99% of you never ask the right questions.
If phosphoglucose isomerase has multi-functions what are they? Phosphoglucose isomerase which is secreted by cells (as opposed to remaining within the cells) thereby giving up it’s well known glycolysis/glucogenesis enzymatic role performs several functions when it finds itself outside the cell of it’s birth. One it behaves as a protein identical to neuroleukin which is a cytokine that causes B cells to mature into antibody-secreting cells. Two as a neuroleukin it behaves as a nerve growth factor that promotes the survival of some embryonic spinal neurons and some sensory nerves. Three it becomes the same protein as autocrine motility factor (AMF), which is a cytokine that stimulates cell migration. Four it may also act as a differentiation and maturation mediator (DMM) that brings about differentiation of human myeloid leukemia cells.
This latter differentiation function is growth inhibiting. It is growth inhibiting for the reason that forcing differentiation stops proliferation.
This article isn’t about phosphoglucose isomerase nor is it meant to explore the concept of “moonlighting proteins” in detail. This article is about Thymosin ß4 which is a “moonlighting protein”. Before we proceed I want you to also take note of the fact that the moonlighting protein we just discussed may act to stimulate cell migration (which is necessary for healing and tissue repair but also for cancer metastis as well). Take note also of it’s ability to be growth inhibiting to cancer in specific tissue. Healing factors that are also moonlightling proteins often have this complexity in their nature. TB4 is no different.
