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Focal adhesions and Ras are functionally and spatially integrated to mediate IL‐1 activation of ERK

In connective tissue cells, IL‐1‐induced ERK activation leading to matrix metalloproteinase (MMP)‐3 expression is dependent on cooperative interactions between focal adhesions and the endoplasmic reticulum (ER). As Ras can be activated on the ER, we investigated the role of Ras in IL‐1 signaling and focal adhesion formation. We found that constitutively active H‐Ras, K‐Ras or N‐Ras enhanced focal adhesion maturation and β1‐integrin activation. IL‐1 promoted the accumulation of Ras isoforms in ER and focal adhesion fractions, as shown in cells cotransfected with GFP‐tagged Ras isoforms and YFP‐ER protein and by analysis of subcellular fractions enriched for ER or focal adhesion proteins. Dominant‐negative H‐Ras or K‐Ras reduced accumulation of H‐Ras and K‐Ras in focal adhesions induced by IL‐1 and also blocked ERK activation and focal adhesion maturation. Ras‐GRF was enriched constitutively in focal adhesion fractions and was required for Ras recruitment to focal adhesions. We conclude that Ras activation and IL‐1 signaling are interactive processes that regulate the maturation of focal adhesions, which, in turn, is required for ERK activation.—Wang, Q., Downey, G. P., McCulloch, C. A. Focal adhesions and Ras are functionally and spatially integrated to mediate IL‐1 activation of ERK. FASEB J. 25, 3448–3464 (2011). www.fasebj.org