Cbl suppresses B cell receptor-mediated phospholipase C (PLC)-gamma2 activation by regulating B cell linker protein-PLC-gamma2 binding.
Accumulating evidence indicates that the Cbl protein plays a negative role in immune receptor signaling; however, the mode of Cbl action in B cell receptor (BCR) signaling still remains unclear. DT40 B cells deficient in Cbl showed enhanced BCR-mediated phospholipase C (PLC)-gamma2 activation, thereby leading to increased apoptosis. A possible explanation for the involvement of Cbl in PLC-gamma2 activation was provided by findings that Cbl interacts via its Src homology 2 (SH2) domain with B cell linker protein (BLNK) after BCR ligation. BLNK is a critical adaptor molecule for PLC-gamma2 tyrosine phosphorylation through its binding to the PLC-gamma2 SH2 domains. As a consequence of the interaction between Cbl and BLNK, the BCR-induced recruitment of PLC-gamma2 to BLNK and the subsequent PLC-gamma2 tyrosine phosphorylation were inhibited. Thus, our data suggest that Cbl negatively regulates the PLC-gamma2 pathway by inhibiting the association of PLC-gamma2 with BLNK.
Yasuda
T
T
Department of Oncology, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan.
Maeda
A
A
Kurosaki
M
M
Tezuka
T
T
Hironaka
K
K
Yamamoto
T
T
Kurosaki
T
T
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism; D002645:Chickens; D004789:Enzyme Activation; D015698:Genomic Library; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007621:Karyotyping; D016297:Mutagenesis, Site-Directed; D050722:Oncogene Protein v-cbl; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D011994:Recombinant Proteins / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; D007527:Isoenzymes; D050722:Oncogene Protein v-cbl; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; D011994:Recombinant Proteins; D015682:Retroviridae Proteins, Oncogenic; D010738:Type C Phospholipases; D051966:Phospholipase C gamma