B cell antigen receptor stimulation induces formation of a Shc-Grb2 complex containing multiple tyrosine-phosphorylated proteins.
Activation of growth factor receptor tyrosine kinases, such as the epidermal growth factor and insulin receptors, induces tyrosine phosphorylation of Shc proteins and their association with the SH2 domain-containing adaptor protein Grb2. The Shc-Grb2 complex has been implicated in coupling these receptors to p21ras. The B cell antigen receptor plays a key role in directing B cell proliferation and differentiation. Although the B cell receptor lacks intrinsic tyrosine kinase activity, its mode of action parallels that of receptor tyrosine kinases in many aspects. B cell receptor stimulation activates src-related tyrosine kinases and the tyrosine kinase syk, which leads to phosphorylation of various cytoplasmic proteins and initiates multiple signaling events, including p21ras activation. Therefore, we have investigated whether Shc proteins are targets for the activated B cell receptor. It was found that the 52- and 46-kDa forms of Shc are expressed in mature human B cells and become rapidly phosphorylated on tyrosine upon B cell receptor stimulation. Also, Shc is induced to associate with the Grb2 molecule and an undefined 130-kDa protein. In a specific response to B cell activation, the Shc-Grb2 complex associates with several tyrosine-phosphorylated proteins, including two prominent phosphoproteins with molecular masses of 130 and 110 kDa. These observations strongly suggest that the Shc and Grb2 adaptor proteins are involved in coupling the B cell antigen receptor to one or multiple signal transduction pathways.
Smit
L
L
Division of Cellular Biochemistry, Netherlands Cancer Institute, Amsterdam.
de Vries-Smits
A M
AM
Bos
J L
JL
Borst
J
J
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D006801:Humans; D051379:Mice; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D011506:Proteins; D011947:Receptors, Antigen, B-Cell; D014443:Tyrosine; D066246:ErbB Receptors; D015689:Oncogene Protein p21(ras)