Dual regulation of BCR-mediated growth inhibition signaling by CD72.
CD72 has been reported to regulate BCR-mediated signals both positively and negatively. SHP-1 and Grb2 bind, respectively, to ITIM1 and ITIM2 of CD72. We generated transformed B cell lines with an immature phenotype following J2 virus infection of splenocytes from CD72(-/-) and wild-type (Wt) mice. The transformed lines were infected with retroviral vectors carrying Tyr (Y) to Phe (F) substitutions in the ITIM sequences (ITIM1 mutated: Y7/F; ITIM2 mutated: Y39/F; and both ITIM mutated: Y7,39/F). Cross-linking of the BCR induced growth inhibition in transfectants expressing Wt CD72, but this response was less sensitive in transfectants with Y7,39/F. The Y7/F transfectants demonstrated the least sensitive response. We were not able to obtain transfectants with Y39/F, suggesting that CD72 associated with SHP-1, but not with Grb2, delivers a strong negative signal. Pre-ligation of CD72, which induces dephosphorylation of the molecule, partially rescued the Wt transfectants from growth inhibition, leading to a growth response profile similar to that of Y7,39/F transfectants. These results suggest that ITIM1/SHP-1 delivers a very strong negative signal that is down-modulated by signals through ITIM2/Grb2, leading to delivery of an attenuated negative signal. Thus, pre-ligation of CD72 results in the manifestation of an ostensible positive signal.
Baba
Takeshi
T
Research Institute for Biological Sciences, Tokyo University of Science (RIKADAI), Noda, Chiba-ken, Japan.
Fusaki
Noemi
N
Aoyama
Akitoshi
A
Li
Daniel H
DH
Okamura
Ross M
RM
Parnes
Jane R
JR
Hozumi
Nobumichi
N
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D005434:Flow Cytometry; D051380:GRB2 Adaptor Protein; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D020929:Mitogen-Activated Protein Kinase Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse