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Blood, 1 July 2007, Vol. 110, No. 1, pp. 3-4.
Important port for SHIP-1 at Dok-3FOX CHASE CANCER CENTER
Dok-3 serves as an inhibitory adaptor protein through recruitment of the 5'-inositol phosphatase, SHIP-1. Ng and colleagues have generated a Dok-3–deficient mouse that exhibits hyperresponsive B cells, thereby implicating the adaptor as an important negative regulator of certain signaling events downstream from the antigen receptor.
In B cells, Dok-3 has been shown to be rapidly tyrosine phosphorylated upon antigen receptor (BCR) engagement, which promotes recruitment of SH2 domain-containing 5'-inositol phosphatase-1 (SHIP-1) to mediate negative signaling (see figure).2,3 Previous reports demonstrated that overexpression of Dok-3 in B-cell lines can suppress BCR-stimulated cytokine production, NFAT activation, and JNK activation, while calcium mobilization and activation of other MAP kinases were unaffected.2,3 In contrast, overexpression of a mutant form of Dok-3 lacking C-terminal tyrosine residues required for SHIP-1 association resulted in enhancement of the same responses upon BCR engagement.2 Csk can also be recruited to tyrosine-phosphorylated Dok-3 (see figure), but this inhibitory protein tyrosine kinase reportedly is not responsible for mediating the negative signaling functions described.2–4 More recent studies have established that tyrosine-phosphorylated Dok-3 can also recruit the Grb2 adaptor (see figure).4,5 Evidence for 2 negative impacts from this interaction have been reported: 1) The Dok-3/Grb2 complex is directly involved in diminishing calcium signaling in response to BCR engagement5; and 2) Dok-3 sequesters Grb2 away from the GTP exchange factor (GEF) Sos, thereby preventing efficient activation of the Ras/ERK cascade.4 Related to the latter report, overexpression of wild-type Dok-3 has been shown to inhibit v-Abl–induced ERK activation and to blunt the transforming capacity of v-Abl.1
In this issue of Blood, Ng and colleagues present the first characterization of B cells from Dok-3–deficient mice. These mice were found to have normal B-cell development, but elevated levels of serum immunoglobulin M (IgM) and potentiated antibody responses to T-independent antigens. Furthermore, the B cells from these mice proliferated significantly more robustly and demonstrated enhanced calcium signaling in response to BCR crosslinking. In addition, BCR-stimulated activation of NF
As an extension of the previous studies in cell lines, the studies of Ng and colleagues significantly improve our understanding of the role of Dok-3 in normal B-cell biology. Furthermore, in contrast to Dok-1, which was previously shown to elicit negative regulation of BCR signaling through Fc
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
B, JNK, and p38 were potentiated in Dok-3–deficient B cells. In contrast to previous studies in cell lines, however, ERK activation was not altered in Dok-3–deficient B cells. Further work is required to establish the basis for the seemingly contradictory impacts on ERK. The authors have also provided evidence that SHIP-1 recruitment to the plasma membrane is normal in Dok-3–deficient B cells, but tyrosine phosphorylation of the enzyme is diminished. This intriguing result suggests that Dok-3 serves as a platform to bring a protein tyrosine kinase in contact with SHIP-1, which is important for activating catalytic function of the inositol phosphatase. 
RIIb, the current work establishes a more direct role for Dok-3 in attenuating BCR signaling responses. Thus, while both Dok-1 and Dok-3 negatively regulate the BCR, they function in a non-redundant manner. 
