Cory G O, Lovering R C, Hinshelwood S, MacCarthy-Morrogh L, Levinsky R J, Kinnon C
Molecular Immunology Unit, University of London, United Kingdom.
J Exp Med. 1995 Aug 1;182(2):611-5. doi: 10.1084/jem.182.2.611.
X-linked agammaglobulinemia, a B cell immunodeficiency, is caused by mutations in the Bruton's tyrosine kinase (Btk) gene. The absence of a functional Btk protein leads to a failure of B cell differentiation and antibody production. B cell receptor stimulation leads to the phosphorylation of the Btk protein and it is, therefore, likely that Btk is involved in B cell receptor signaling. As a nonreceptor tyrosine kinase, Btk is likely to interact with several proteins within the context of a signal transduction pathway. To understand such interactions, we have generated glutathione S-transferase fusion proteins corresponding to different domains of the human Btk protein. We have identified a 120-kD protein present in human B cells as being bound by the SH3 domain of Btk and which, after B cell receptor stimulation, is one of the major substrates of tyrosine phosphorylation. We have shown that this 120-kD protein is the protein product of c-cbl, a protooncogene, which is known to be phosphorylated in response to T cell receptor stimulation and to interact with several other tyrosine kinases. Association of the SH3 domain of Btk with p120cbl provides evidence for an analogous role for p120cbl in B cell signaling pathways. The p120cbl protein is the first identified ligand of the Btk SH3 domain.
X连锁无丙种球蛋白血症是一种B细胞免疫缺陷病，由布鲁顿酪氨酸激酶（Btk）基因突变引起。功能性Btk蛋白的缺失导致B细胞分化和抗体产生失败。B细胞受体刺激导致Btk蛋白磷酸化，因此Btk可能参与B细胞受体信号传导。作为一种非受体酪氨酸激酶，Btk可能在信号转导途径中与多种蛋白质相互作用。为了了解这种相互作用，我们制备了与人Btk蛋白不同结构域相对应的谷胱甘肽S-转移酶融合蛋白。我们鉴定出一种存在于人B细胞中的120-kD蛋白，它被Btk的SH3结构域结合，并且在B细胞受体刺激后，是酪氨酸磷酸化的主要底物之一。我们已经证明这种120-kD蛋白是原癌基因c-cbl的蛋白产物，已知其在T细胞受体刺激后被磷酸化，并与其他几种酪氨酸激酶相互作用。Btk的SH3结构域与p120cbl的结合为p120cbl在B细胞信号通路中的类似作用提供了证据。p120cbl蛋白是第一个被鉴定的Btk SH3结构域的配体。
