Although cell-autonomous activation of ErbB signaling in mature astrocytes induced spontaneous astrogliosis with canonical features (Figure 4), inhibiting ErbB signaling in reactive astrocytes specifically suppressed their ability to develop hypertrophy (Figure 2). To investigate which signaling pathways mediated the effects of ErbB activation on the hypertrophy of reactive astrocytes, ErbB-activated downstream signaling proteins were examined in the injured cortices of Mlc1-dnEGFR and littermate control mice. Interestingly, WB revealed no reductions in phosphorylated Akt, Erk or STAT3, despite the fact that ErbB3 activity was reduced in injured tissues of Mlc1-dnEGFR mice (Figure 7a and b). Instead, phosphorylation of FAK and Src was significantly suppressed in injured tissues from Mlc1-dnEGFR mice (Figure 7a and b). Further, immunostaining revealed that stab wound injury in control brains induced upregulation of the active forms of FAK (pY861, pY397 and pY925) and Src (pY418) specifically in reactive astrocytes (Figure 7c and Supplementary Figure S12). However, both the number of cells with active FAK or Src and the average activity per cell were significantly reduced in the injured cortices of Mlc1-dnEGFR mice (Figure 7c–e). In concordance with the dnEGFR-induced suppression of reactive astrocytic expansion, phosphorylation of profilin, as well as its upstream regulating kinase ROCK , were suppressed in the injured cortices of Mlc1-dnEGFR mice (Figure 7a and b). Consistent with the finding that hypertrophic remodeling did not rely on GFAP expression (Figure 2), the discovery of a Src/FAK/profilin signaling pathway emphasized the involvement of active actin remodeling in the reactive responses of astrocytes.