Two adaptor proteins prevent cells from overreacting to bacterial lipopolysaccaride (LPS), report Shinohara et al. on page 333. Dok-1 and Dok-2 dampen intracellular signals from the LPS receptor, Toll-like receptor 4 (TLR4), which may help explain how cells mount a potent response to invading bacteria without also triggering destructive inflammatory responses.
Dok-1 and Dok-2 are adaptor proteins found in hematopoietic cells that are activated by tyrosine kinases in response to antigen and cytokine receptor signals. Once activated, they suppress intracellular signals by inhibiting the GTPase Ras, thereby keeping cellular activation and multiplication under control. The importance of this control is evident in mice lacking both proteins, which have been shown to develop leukemia.
Shinohara et al. now provide evidence that these proteins also inhibit LPS-induced TLR4 signals. Dok-1 and Dok-2 are tyrosine phosphorylated within 1 minute of LPS treatment, and cells lacking either protein...
