Mauno Vihinen¹, Pekka T. Mattsson^2,3 and C. I. Edvard Smith²

¹Department of Biosciences, Division of Biochemistry, P. O. Box 56, FIN-00014 University of Helsinki, Finland

²Center for BioTechnology, Department of Bioscience at Novum, Karolinska Institute, S-141 57 Huddinge and Department of Immunology, Microbiology, Pathology and Infectious Diseases (IMPI), Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden

³Department of Biochemistry and Food Chemistry, University of Turku, Vatselankatu 2, Arcanum, FIN-20014 Turku, Finland

Received 11/24/96; Accepted 12/16/96; On-line 01/01/97

4. THE XLA GENE ENCODES A TYROSINE KINASE

In the 1980s the gene defective in XLA was mapped to the Xq21.3-22 region in the mid-portion of the long arm of the X-chromosome. In particular, the marker DXS178 proved to be useful as it segregated with the disease gene in all families analyzed (10, 11). This marker was also crucial in the positional cloning of the XLA gene as it was used in the selection of yeast artificial chromosomes which later was employed in the enrichment of cDNAs from B lineage cell lines (6). Two missense mutations affecting critical regions in the kinase domain as well as gross deletions in the gene demonstrated that the isolated gene in fact encoded the disease gene (6). In a search for novel tyrosine kinases, a new gene was found to map to the X chromosomal region implicated in XLA (7). These authors demonstrated the absence of mRNA as well as the corresponding protein in some patients, thus strongly implicating this gene as the gene defective in XLA. Although initially different names were employed in the two cloning papers, it was later agreed to use a common name, Btk.

BTK was found to encode a cytoplasmic protein-tyrosine kinase (PTK). These kinases are sometimes called non-receptor PTKs to distinguish them from the membrane-bound receptor PTKs such as platelet-derived growth factor receptor (PDGFR). Btk resembles Src, but forms a distinct family together with Tec and Itk (Table 1). A fourth member was later isolated from human bone marrow and was designated Bmx (12). It has been suggested that Txk (13, 14) also belongs to this family. These proteins are called the Tec family, as Tec was the first kinase of this family to be isolated (15). The family has the following characteristics:

• (i) in the N-terminus, there is a region designated pleckstrin homology (PH) domain. This region is believed to have a membrane-localizing function. In the Src family myristylation in the N-terminus serves this function, but the Tec family kinases lack a myristylation consensus sequence.

• (ii) the PH domain is followed by the TH region, which is unique to the Tec family.

• (iii) Between the C-terminus and the TH region there are three domains, SH (Src homology) 3, 2 and 1, showing the same order as in Src (Fig. 2). The SH2 and SH3 domains have binding functions, whereas the SH1 (kinase) domain is catalytic which enables these enzymes to phosphorylate tyrosine residue(s). In contrast to Src family members, but similar to other non-Src kinases, Btk lacks a regulatory tyrosine residue in the C-terminus.

Figure 2. Domain organization of Btk and Src family of kinases.