Positive signaling through CD72 induces mitogen-activated protein kinase activation and synergizes with B cell receptor signals to induce X-linked immunodeficiency B cell proliferation

CD72 is a 45-kDa B cell transmembrane glycoprotein that has been shown to b e important for B cell activation. However, whether CD72 ligation induces B cell activation by delivering positive signals or sequestering negative si gnals away from B cell receptor (BCR) signals remains unclear. Here, by com paring the late signaling events associated with the mitogen-activated prot ein kinase pathway, we identified many similarities and some differenes bet ween CD72 and BCR signaling. Thus, CD72 and BCR activated the extracellular signal-regulated kinase (ERK) and the c-jun N-terminal kinase (JNK) but no t p38 mitogen-activated protein kinase. Both CD72- and BCR-mediated ERK and JNK activation required protein kinase C activity, which was equally impor tant for CD72- and BCR-induced B cell proliferation. However, CD72 induced stronger JNK activation compared with BCR. Surprisingly, the JNK activation induced by both BCR and CD72 is Btk independent. Although both CD72 and BC R induced Btk-dependent ERK activation, CD72-mediated proliferation is more resistent to blocking of ERK activity than that of BCR, as shown by the pr oliferation response of B cells treated with PD98059 and dibutyryl cAMP, ag ents that inhibit ERK activity. Most importantly, CD72 signaling compensate d for defective BCR signaling in X-linked immunodeficiency B cells and part ially restored the proliferation response of X-linked immunodeficiency B ce lls to anti-IgM ligation. These results suggest that CD72 signals B cells b y inducing BCR-independent positive signaling pathways.