Abstract
Sema4D-induced activation of plexin-B1 has been reported to evoke different and sometimes opposing cellular responses. The mechanisms underlying the versatility of plexin-B1-mediated effects are not clear. Plexin-B1 can associate with the receptor tyrosine kinases ErbB-2 and Met. Here we show that Sema4D-induced activation and inactivation of RhoA require ErbB-2 and Met, respectively. In breast carcinoma cells, Sema4D can have pro- and anti-migratory effects depending on the presence of ErbB-2 and Met, and the exchange of the two receptor tyrosine kinases is sufficient to convert the cellular response to Sema4D from pro- to anti-migratory and vice versa. This work identifies a novel mechanism by which plexin-mediated signaling can be regulated and explains how Sema4D can exert different biological activities through the differential association of its receptor with ErbB-2 and Met.
Highlights
The activation of plexins by semaphorins initiates a variety of signaling processes that involve several small GTPases of the Ras and Rho families [14, 15]
It has been shown that Sema4D-induced plexin-B1 activation can result either in activation or inhibition of RhoA [20, 30]
As described before [21,22,23, 26], Sema4D stimulation of HEK cells expressing plexin-B1 and PDZ-RhoGEF and kept at 0.5 or 1.5% FBS led to a strong RhoA activation, which was accompanied by tyrosine phosphorylation of plexin-B1 and endogenous ErbB-2 and which could be blocked by the ErbB-2 inhibitor AG1478 (Fig. 1, left and middle panels)
Summary
The activation of plexins by semaphorins initiates a variety of signaling processes that involve several small GTPases of the Ras and Rho families [14, 15]. As described before [21,22,23, 26], Sema4D stimulation of HEK cells expressing plexin-B1 and PDZ-RhoGEF and kept at 0.5 or 1.5% FBS led to a strong RhoA activation, which was accompanied by tyrosine phosphorylation of plexin-B1 and endogenous ErbB-2 and which could be blocked by the ErbB-2 inhibitor AG1478 (Fig. 1, left and middle panels).
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