Abstract
The actin filament-associated protein of 110 kDa (AFAP-110) is a Src binding partner that represents a potential modulator of actin filament integrity in response to cellular signals. Previous reports have demonstrated that AFAP-110 is capable of directly binding and altering actin filaments. Deletion of the leucine zipper motif of AFAP-110 (AFAP-110Δlzip) has been shown to induce a phenotype which resembles Src-transformed cells, by repositioning actin filaments into rosettes. This deletion also mimics a conformational change in AFAP-110 that is detected in Src-transformed cells. The results presented here indicate that unlike AFAP-110, AFAP-110Δlzip is capable of activating cellular tyrosine kinases, including Src family members, and that AFAP-110Δlzip itself is hyperphosphorylated. The newly tyrosine phosphorylated proteins and activated Src-family members appear to be associated with actin-rich lamellipodia. A point mutation that alters the SH3-binding motif of AFAP-110Δlzip prevents it from activating tyrosine kinases and altering actin filament integrity. In addition, a deletion within a pleckstrin homology (PH) domain of AFAP-110Δlzip will also revert its effects upon actin filaments. Lastly, dominant-positive RhoAV14 will block the ability of AFAP-110Δlzip from inducing actin filament rosettes, but does not inhibit Src activation. Thus, conformational changes in AFAP-110 enable it to activate cellular kinases in a mechanism requiring SH3 and/or PH domain interactions. We hypothesize that cellular signals which alter AFAP-110 conformation, enable it to activate cellular kinases such as cSrc, which then direct changes in actin filament integrity in a Rho-dependent fashion.
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Acknowledgements
Thanks to Ray Mattingly, Wayne State University for the dominant-positive RhoAV14 constructs. This work was supported by a grant from the NCI (to DC Flynn), CA60731. JM Baisden was supported by a grant from the West Virginia University Medical Scientist Training Program.
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Baisden, J., Gatesman, A., Cherezova, L. et al. The intrinsic ability of AFAP-110 to alter actin filament integrity is linked with its ability to also activate cellular tyrosine kinases. Oncogene 20, 6607–6616 (2001). https://doi.org/10.1038/sj.onc.1204802
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DOI: https://doi.org/10.1038/sj.onc.1204802
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