TEC family kinases in health and disease - Loss-of-function of BTK and ITK and the gain-of-function fusions ITK-SYK and BTK-SYK

Abstract

The TEC family is ancient and constitutes the second largest family of cytoplasmic tyrosine kinases. In 1993, loss-of-function mutations in the BTK gene were reported as the cause of X-linked agammaglobulinemia. Of all the existing 90 tyrosine kinases in humans, Bruton's tyrosine kinase (BTK) is the kinase for which most mutations have been identified. These experiments of nature collectively provide a form of mutation scanning with direct implications for the several hundred endogenous signaling proteins carrying domains also found in BTK. In 2009, an inactivating mutation in the ITK gene was shown to cause susceptibility to lethal Epstein-Barr virus infection. Both kinases represent interesting targets for inhibition: in the case of BTK, as an immunosuppressant, whereas there is evidence that the inhibition of inducible T-cell kinase (ITK) could influence the infectivity of HIV and also have anti-inflammatory activity. Since 2006, several patients carrying a fusion protein, originating from a translocation joining genes encoding the kinases ITK and spleen tyrosine kinase (SYK), have been shown to develop T-cell lymphoma. We review these disease processes and also describe the role of the N-terminal pleckstrin homology-Tec homology (PH-TH) domain doublet of BTK and ITK in the downstream intracellular signaling of such fusion proteins. BTK and ITK are TEC-family kinases. In 1993 loss-of-function mutations in the BTK gene were reported as the cause of X-linked agammaglobulinemia (XLA) and in 2009 an inactivating mutation in the ITK gene was shown to cause susceptibility to lethal Epstein-Barr virus infection. Recently, a tumor-causing, gain-of-function fusion in ITK-SYK was described. Both ITK and BTK represent interesting targets for inhibition. © 2011 FEBS.