Receptor Tyrosine Kinase links to MAPKinase

MAP kinase is a well known pain chemical and is discussed in multiple articles here. Ret links to MAPK.


High energy phosphate bonds are the batteries on which the body runs. These high energy phosphates transfer electrons to other chemicals in the body and change them from inert to active.

Reiterating, a kinase is an enzyme which phosphorylates, or links high energy phosphate bonds to chemicals, such as proteins (chains of amino acids greater than 200 in length) to make them active. Peptides, which are chains less than 200 amino acids in links can also be activated by phosphorylation. ATP is not the only phosphorylater but is the most important. Once it is activated by three high energy phosphates, it hands one off and become ADP.

Thus, the prime example of such an energized compound is ATP (adenosine triphosphate), well known as a product of the Krebs (citric acid) cycle which turns out 36 molecules of ATP at every turn, and is at the heart of metabolic activity in the body. We manufacture 45% of our body weight in ATP every day. This shows how important ATP is to metabolism.

One type of receptor on cell surfaces often uses tyrosine kinase, ie. it attaches high energy bonds to tyrosine amino acids. These are called Receptor Tyrosine Kinases, or Ret.

Ret is made of a very large extracellular protein mass, or N terminal region, which is an immunoglobulin. It crosses the cell membrane with a relatively small (about 40 amino acid) domain, and ends at the intracellular portion, the C terminal region, which does the phosphorylating (kinase activity). The Ret tyrosine kinase is termed RTK.

When a nerve growth factor binds to the extracellular N terminal mass, two RTK’s join (dimer). The RTK dimer then has an affinity for phospholipase C and Src proteins. Then certain adaptor proteins link the activation of RTK to signal transduction pathways, such as the MAPKinase pathway signalling cascade.

Ret has its origin in the Runx1 genes (which are part of the Runt gene family). These genes also play a role in differentiation of neuronal (as well as blood forming) cells into sensory neurons, specially pain neurons (nociceptors). In fetal life Runx1 related activity also determines how deeply the sensory neuron will penetrate into the layers of the spinal cord. The more Runx, the deeper it goes. Runx also affects differentiation of sensory neurons in the dorsal root ganglion (DRG), presumably determining which neurons will act as nociceptors and to what degree of sensitization.

One has to wonder if injury to nerves affects the metabolism and activity of Runx1, a facilitator of nociceptor penetration to the deeper dorsal horn. For example, might injury impair access of incoming pain neurons to the deeper layers of the cord. The deeper layers are where descending, inhibitory interneurons synapse as the pain signal crosses to the opposite side of the cord. Might incoming signal in injured nociceptors preferentially shunt to pathways on the same side of the cord? (eg. the superficial Rexed Layer I, or marginal layer), the superficial ascending pathways being predominantly excitatory rather than inhibitory. It is noted that Runx knockout mice do not develop neuropathic pain easily. (Runx knockin therapy is currently under consideration for treatment of leukemic white cells).

Ret is the receptor for glial cell derived neurotrophic factor (GDNF). Before GDNF can activate Ret, it has to bind to a co-receptor glycosylphosphatidylinositol (GFRalpha) to form a complex. This complex hooks two Rets together, which effects the phosphorylation of kinases, such as MAPK. MAPK is a signal transduction pathway.

Here is another area where research in cancer, which enjoys huge funding, may benefit pain research, which has very little funding.

Because Runx1 (one of the Runt genes) and Ret are important in cancer, especially leukemias or other cancers of blood forming cells, the mechanisms of Runx and Ret manipulation are being vigorously studied. When we can manipulate Runx1, we may be able to eliminate neuropathic pain, as seen in Runx1 knockout mice.

We are not dead in the water on pain. We are just charity cases, hoping for a few crumbs to fall from the tables of the masters. Of course, it could just as easily be the other way around, since more is spent on pain than ANY OTHER MEDICAL CONDITION, but cancer is the biggest baddest boy in town, or is it? Which is the greater evil? Is it death, or intractable pain? One is visible and the other is not, but that does not necessarily answer the question. Nature did not give us an organ to feel the pain of OTHERS, but it did give us the means to perceive OUR OWN pain.