Epithelial to mesenchymal transition (EMT) is important in normal development, wound healing and cancer. The long-term goal of this work is to study cell migration and EMT in the context of wounds and cancer (a type of unhealed wound). Src family kinases (SFK) play a key role in regulating cell migration through the phosphorylation of actin binding proteins, like cortactin. In the previous funding period, we discovered that the Src substrate and cortactin homolog, mammalian actin-binding protein 1 (mAbp1), impairs cell migration downstream of Src. Little is known about how SFKs or their substrates negatively regulate cell migration and invasion. Using yeast two-hybrid (Y2H) we identified novel mAbp1 binding partners including four-and-a-half LIM domain protein-2 (FHL2) that binds to the N-terminus of mAbp1 and cyclase associated protein-1 (CAP1) that binds to the SH3 domain of mAbp1. We found that FHL2 and CAP1-deficient cells have impaired invasive migration, suggesting that mAbp1 may inhibit invasion by sequestering FHL2 or CAP1. This is particularly interesting because FHL2, cortactin and CAP1 have all been implicated in cancer progression. We hypothesize that mAbp1 impairs cell invasion and EMT through inhibitory effects on FHL2 and CAP1/cortactin signaling. In support of this proposal we have made the following recent advances: 1. We have developed a zebrafish model to study EMT during epithelial cell transformation and wounding to probe the parallels between cell transformation (as an unhealed wound) and wound healing. 2. We have identified FHL2 as a key factor that is up-regulated during wounding and epithelial cell transformation, and identify an important role for FHL2 in EMT in vivo. Based on this progress we will now test how mAbp1, FHL2 and CAP1 regulate cell migration in cell culture systems, and during EMT using zebrafish.
The proposed research contributes to human health by increasing our understanding of cell signaling and cell migration in the context of wound healing and cancer progression. We have identified a novel signaling pathway through the actin binding protein mAbp1 and an oncoprotein FHL2 that regulates epithelial cell migration and cancer invasion.
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