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Physical and functional characterization of the genetic locus of IBtk, an inhibitor of Bruton's tyrosine kinase: evidence for three protein isoforms of IBtk*

Posted by on in 2008
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Spatuzza, Carmen 1, Marco Schiavone1, Emanuela Di Salle2, Elzbieta Janda1, Marco Sardiello3, Giuseppe Fiume1, Olga Fierro4, Marco Simonetta2, Notis Argiriou2, Raffaella Faraonio2, Rosanna Capparelli5, Ileana Quinto1,* and Giuseppe Scala1, 2008, Nucleic Acids Research 36(13):4402-4416.


1Department of Experimental and Clinical Medicine, University of Catanzaro ‘Magna Graecia’, 88100 Catanzaro, 2Department of Biochemistry and Medical Biotechnology, University of Naples ‘Federico II’, 3Telethon Institute of Genetics and Medicine, 80131 Naples, 4Institute of Food Sciences, CNR, Avellino and 5Department of Biotechnological Sciences, University of Naples ‘Federico II’, Naples, Italy

*To whom correspondence should be addressed. Tel: +39 0961 3694058 (office); Fax: +39 0961 3694090; Email: quinto@unicz.it Correspondence may also be addressed to Giuseppe Scala. Tel: +39 0961 3694059 (office); Fax: +39 0961 3694090; Email: scala@unicz.it

Abstract

Bruton's tyrosine kinase (Btk) is required for B-cell development. Btk deficiency causes X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Btk lacks a negative regulatory domain and may rely on cytoplasmic proteins to regulate its activity. Consistently, we identified an inhibitor of Btk, IBtk, which binds to the PH domain of Btk and down-regulates the Btk kinase activity. IBtk is an evolutionary conserved protein encoded by a single genomic sequence at 6q14.1 cytogenetic location, a region of recurrent chromosomal aberrations in lymphoproliferative disorders; however, the physical and functional organization of IBTK is unknown. Here, we report that the human IBTK locus includes three distinct mRNAs arising from complete intron splicing, an additional polyadenylation signal and a second transcription start site that utilizes a specific ATG for protein translation. By northern blot, 5'RACE and 3'RACE we identified three IBTK, IBTKβ and IBTK mRNAs, whose transcription is driven by two distinct promoter regions; the corresponding IBtk proteins were detected in human cells and mouse tissues by specific antibodies. These results provide the first characterization of the human IBTK locus and may assist in understanding the in vivo function of IBtk.

*Note: Custom peptides and IgY antibodies used in this publication were produced by Gallus Immunotech Inc. Please visit our Custom Peptide Synthesis and  Custom IgY production page for more information.

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