Manié S N, Sattler M, Astier A, Phifer J S, Canty T, Morimoto C, Druker B J, Salgia R, Griffin J D, Freedman A S
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Exp Hematol. 1997 Jan;25(1):45-50.
Integrin crosslinking on human B cells induces tyrosine phosphorylation of a set of proteins ranging from 105 to 130 kDa, among which is the focal adhesion kinase p125FAK. Here we show that the c-CBL protooncogene product p120c-CBL is a component of these substrates. beta 1 integrin stimulation of p120c-CBL phosphorylation was observed in both transformed and normal human B cells, and was inhibited by prior treatment of cells with cytochalasin B, which disrupts the actin network. In contrast, tyrosine phosphorylation of p120c-CBL following crosslinking of the B cell antigen receptor (BCR) was not affected by cytochalasin B. Integrin stimulation of the promegakaryocytic cell line MO7e also led to a cytoskeleton-dependent tyrosine phosphorylation of p120c-CBL. In MO7e cells, this stimulation was induced by ligation of either beta 1 or beta 2 integrin, whereas only by ligation of beta 1 integrin in B cells. Tyrosine phosphorylation of p120c-CBL links phosphatidylinositol-3 kinase (PI-3K) with the BCR signaling machinery. Although the p85 subunit of PI-3K was increased in p120c-CBL immunoprecipitates from BCR-stimulated B cells, this association was only minimally increased by beta 1 integrin ligation. The function of p120c-CBL remains unknown; however, its interactions in vitro and in vivo with Src homology 2 and 3 (SH2 and SH3) domain-containing proteins suggest that p120c-CBL has a significant function in signal transduction pathways, and therefore may play a role in integrin signaling in lymphoid and hematopoietic cells.
人B细胞上的整合素交联可诱导一组分子量在105至130 kDa之间的蛋白质发生酪氨酸磷酸化，其中包括粘着斑激酶p125FAK。本文我们表明c-CBL原癌基因产物p120c-CBL是这些底物的一个组成部分。在转化的和正常人B细胞中均观察到β1整合素刺激p120c-CBL磷酸化，并且该过程受到细胞松弛素B预处理的抑制，细胞松弛素B会破坏肌动蛋白网络。相反，B细胞抗原受体（BCR）交联后p120c-CBL的酪氨酸磷酸化不受细胞松弛素B的影响。前巨核细胞系MO7e的整合素刺激也导致p120c-CBL发生细胞骨架依赖性酪氨酸磷酸化。在MO7e细胞中，这种刺激是由β1或β2整合素的连接诱导的，而在B细胞中仅由β1整合素的连接诱导。p120c-CBL的酪氨酸磷酸化将磷脂酰肌醇-3激酶（PI-3K）与BCR信号传导机制联系起来。尽管PI-3K的p85亚基在BCR刺激的B细胞的p120c-CBL免疫沉淀物中有所增加，但β1整合素连接仅使其这种关联略有增加。p120c-CBL的功能仍然未知；然而，其在体外和体内与含Src同源2和3（SH2和SH3）结构域的蛋白质的相互作用表明，p120c-CBL在信号转导途径中具有重要功能，因此可能在淋巴细胞和造血细胞的整合素信号传导中发挥作用。
