Fig. (1) Regulation of RA FLS activation by Ras family GTPases. In RA FLS, the H-Ras –specific GEF RasGRF1 is over-expressed. Furthermore, unidentified cellular proteases cleave RasGRF1, resulting in its constitutive activation. This leads to H-Ras activation, promoting high basal transcription of IL-6 and MMP-3. Exposure of RA FLS to inflammatory cytokines leads to further activation of H-Ras, as well as inducing activation of K-Ras and N-Ras. Through their combined and redundant activation of MAP kinase and PI3-kinase signaling pathways, H-, K-, and N-Ras each contribute to RA FLS chemokine, cytokine, and MMP production that perpetuates inflammation and promotes disease progression.