Abstract
Bruton's tyrosine kinase (Btk), a member of the Tec family of protein-tyrosine kinases, has been shown to be crucial for B cell development, differentiation, and signaling. Mutations in the Btk gene lead to X-linked agammaglobulinemia in humans and X-linked immunodeficiency in mice. Using a co-transfection approach, we present evidence here that Btk interacts physically with caveolin-1, a 22-kDa integral membrane protein, which is the principal structural and regulatory component of caveolae membranes. In addition, we found that native Bmx, another member of the Tec family kinases, is associated with endogenous caveolin-1 in primary human umbilical vein endothelial cells. Second, in transient transfection assays, expression of caveolin-1 leads to a substantial reduction in the in vivo tyrosine phosphorylation of both Btk and its constitutively active form, E41K. Furthermore, a caveolin-1 scaffolding peptide (amino acids 82--101) functionally suppressed the autokinase activity of purified recombinant Btk protein. Third, we demonstrate that mouse splenic B-lymphocytes express substantial amounts of caveolin-1. Interestingly, caveolin-1 was found to be constitutively phosphorylated on tyrosine 14 in these cells. The expression of caveolin-1 in B-lymphocytes and its interaction with Btk may have implications not only for B cell activation and signaling, but also for antigen presentation.
Highlights
Bruton’s tyrosine kinase (Btk)1 is a member of the Tec family of nonreceptor protein-tyrosine kinases (PTKs) [1,2,3,4]
We find that Btk contains a potential candidate caveolin-binding motif (WXFXXXXW) within its catalytic domain (Fig. 1A)
We describe the in vivo interaction of two members of the Tec family kinases, Btk and Bmx, with the membrane-organizing coat protein, caveolin-1
Summary
Bruton’s tyrosine kinase (Btk) is a member of the Tec family of nonreceptor protein-tyrosine kinases (PTKs) [1,2,3,4]. A 20-amino acid juxtamembrane region, called the scaffolding domain, in the N-terminal region of the protein (residues 82–101) has been shown to mediate the association of caveolin with the bulk of relevant signaling molecules [23]. Among these are G-proteins (␣ and ␥ subunits), Ha-Ras, Fyn, Erk-2, epidermal growth factor, platelet-derived growth factor, tumor necrosis factor receptor-associated factor 2, endothelial nitric-oxide synthase, protein kinase C isoforms, insulin and Neu (c-ErbB2) receptors, and Src family tyrosine kinases (24 –34). The functional significance of a bona fide caveolin-binding motif in this family of tyrosine kinases warrants functional characterization, with respect to its role in signal transduction
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