title: 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.
authors.affiliation: Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Huddinge University Hospital, Sweden.
authors.forename: Alamdar
authors.initials: A
authors.lastname: Hussain
authors.forename: Liang
authors.initials: L
authors.lastname: Yu
authors.forename: Rani
authors.initials: R
authors.lastname: Faryal
authors.forename: Dara K
authors.initials: DK
authors.lastname: Mohammad
authors.forename: Abdalla J
authors.initials: AJ
authors.lastname: Mohamed
authors.forename: C I Edvard
authors.initials: CI
authors.lastname: Smith
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000201:enzymology / Q000235:genetics; D000818:Animals; D004789:Enzyme Activation; D020031:Epstein-Barr Virus Infections / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000201:enzymology / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D011993:Recombinant Fusion Proteins; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C080813:emt protein-tyrosine kinase