The role of SWAP-70 in mast cell adhesion, migration and F-actin cytokeletal rearrangements

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Migration and adhesion of mast cells (MCs) is essential for their function and must be properly regulated, F-actin dynamics and adhesion receptors are to be controlled. Earlier we demonstrated the F-actin binding protein SWAP-70 as an important modulator of MC migration and adhesion. In the 1st funding period we identified a novel interaction and two novel mechanisms with which SWAP-70 controls F-actin rearrangements: (i) direct physial interaction with the F-actin severing protein cofilin and restriction of its activity, and (ii) bundling and stabilization of actin filaments by SWAP-70. Also, we further characterized SWAP-70 control of integrins and showed their physical interaction with SWAP-70. Furthermore, we accumulated evidence for a hitherto largely unknown function of cadherins, i.e. E-Cdh, in MCs and a MCspecific E-Cdh deficient mouse strain is being generated. Indications now emerged for partially overlapping functions of SWAP-70 and its only closely related protein, DEF6. The Swap-70-/- Def6-/- strain was generated and its MC will now be analyzed in vivo and in vitro. In addition, a MC-specific SWAP-70 deficient mouse strain was generated based on Mcpt5-Cre expression in Swap-70floxed mice. This new strain will eliminate bystander effects of other SWAP-70 deficient cell types. Together, in the 2nd funding period, we will further analyze control of integrins by SWAP-70, will explore the newly identified SWAP-70 control of cofilin, will determine the function of E-Cdh in MCs and the role of SWAP-70 therein, and will include analysis of DEF6 and its relationship to SWAP-70 in MCs. With this program we expect to contribute significantly to our understanding of central pathways and mechanisms that govern MC migration and adhesion.