What Human Mutations in Kinase Genes May Be Telling Us about Approaches to Personalized Nutrition, Novel Nutritional Therapies, and Mom’s Advice to Eat Your Vegetables
Reversible phosphorylation of proteins regulates almost every aspect of cellular life. This includes signal transduction events responsible for human sensory perception, such as sight, hearing, pain, smell, and taste. Abnormal over phosphorylation is a cause or consequence of many chronic illnesses including arthritis, the metabolic syndrome, Type 2 diabetes, obesity, and most cancers. Over phoshorylation is known to be a result of mutations or metabolic dysregulation of specific protein kinases and phosphatases which exert their effects by altering the phosphorylation state of intracellular proteins which upregulate inflammation, modulate metabolism, and control gene expression. The specific phosphorylation of key regulatory proteins and their targets are highly correlated to certain disease states.
A striking example is agammaglobulinemia, an X-linked human disease which is seen as an absence of mature B cells and reduced serum antibodies. Curiously these individuals are resistant to autoimmune diseases such as rheumatoid arthritis. Similarly, RA patients treated with agents that reduce B cells see marked improvement of symptoms. It was discovered that agammaglobulinemia results from a single mutation in the tyrosine kinase gene, Bruton tyrosine kinase (BTK). In mice where BTK has been inactivated (Xid), a 50% reduction of B cells occurs and the B cells that do exist are abnormal in antigen (e.g., LPS) induced inflammation. Molecular signaling studies have shown that BTK actives inflammation by signaling through to the NFkB pathway. Partial replacement of Btk activity (25%) in Xid animals is sufficient to normalize B cell development but reduces NFkB pathway signaling, suggesting that the degree of Btk function is important in allowing effective B cell activation in response to antigen. Further, a window may exist between halting B cell development and reducing B cell signaling; hence targeting the kinase function of Btk and kinases that cross-talk with Btk such as Syk and BmK, could result in desensitization of B cell signaling and possibly provide a therapeutic approach to autoimmune diseases such as RA where BTK-activated NFkB signaling is required for progression of the disease.
Conversely, it is know that populations that consume high levels of phytochemicals have lower incidences of inflammatory disease. A great deal of evidence is emerging that the specific amount and type of phytochemicals in the diet may be responsible. For example the literature is replete with articles reporting that the Mediterranean style diet rich in phytochemicals correlate with reduced risks of metabolic syndrome, cardiovascular disease, inflammation, and cancer. While this field is still young, reports are emerging that several phytochemicals in the Mediterranean style diet may be protein kinase modulators in vivo.
Many labs have been screening ingredients found in the human food chain in cell-based disease models to assay their potential as therapeutics. Bioassay readouts (biomarkers) can be designed to predict their potential as treatments for conditions with underlying causes such as inflammation, insulin resistance, and endothelial dysfunction. Over 10,000 phytochemicals have been identified using these research tools, the question however is which ones are candidates for human therapies. Some laboratories are evaluating lead candidates for their inhibitory effects on Btk, Syk, Bmk, and others which inhibit NFkB directed inflammatory disease. Recently work in our laboratory resulted in the discovery of a natural pharmacophore from hops, a substituted 1-3 cyclopentodione, that not only inhibits activation of the NFkB pathway, but also is a Btk, Syk, and BmK multitarget kinase inhibitor. We found molecules of this pharmacophore family inhibit inflammation in a mouse model of arthritis. Work in human subjects with rheumatoid arthritis is also showing great promise.
Looking at a bigger picture, it is feasible that specific phytochemicals consumed by certain populations may well be reducing their incidence of autoimmune disease such as RA by cooling down B cell/BTK induced activation of NFkB. Mom always said to eat your vegetables – we are now beginning to better understand her infinite wisdom and that of Mother Nature….