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.
Hussain A, Yu L, Faryal R, Mohammad DK, Mohamed AJ, Edvard Smith CI.
FEBS J. 2011 Apr 23. doi: 10.1111/j.1742-4658.2011.08134.x. [Epub ahead of print]
The TEC-family constitutes an ancient and 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 (XLA). Out of all the existing 90 tyrosine kinases in humans, BTK is the kinase where most mutations have been identified. These experiments of nature collectively provide a form of mutation scanning with direct implications for those 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 (EBV). Both kinases represent interesting targets for inhibition; in the case of BTK as an immunosuppressant, while there is evidence that inhibition of 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 SYK, were found to develop T-cell lymphoma. We review these disease processes and also describe the role of the N-terminal PH-TH domain doublet of BTK and ITK in the downstream intracellular signaling of such fusion proteins.
Source:
1Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Huddinge, Sweden, 2Department of Hematology, Huaian NO. 1 hospital, Nanjing Medical University, Huaian, Jiangsu, China, 3Department of Biosciences, COMSATS Institute of Information Technology, Chak Shahzad Campus, Islamabad, Pakistan, 4Faculty of Science (Biology), Universiti Brunei Darussalam, Jalan Tungku Link, Gadong BE1410, Brunei Darussalam.
Accessed full article at http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2011.08134.x/pdf