All cancer cells have one thing in common - they change shape. Morphology is largely governed by components of the cytoskeleton, such as actin filaments, and oncogenes like Src will alter actin filament integrity. However, the mechanisms by which Src directly affects actin filament structures are unknown. The Src-associated substrate AFAP-110 (actin filament-associated protein, 110 kDa) was originally characterized as an SH2/SH3 binding partner for Src and has been hypothesized to modulate the effects of Src upon actin filaments. A role for AFAP-110 in altering actin filament integrity was revealed by mutagenesis of a carboxy-terminal leucine zipper motif, which enabled AFAP-110 to disrupt actin filaments in vivo and in vitro. AFAP-110 also associates with lamellipodia and membrane ruffles, indicating a potential role in the formation of these structures. Src527F expression will affect the conformation of AFAP-110, which may activate and enable it to alter actin filament integrity. Thus, the ability of AFAP-110 to alter actin filament structures may be activatable and evidence support a potential role for the p2l-activated kinase Pak in this pathway. We hypothesize that AFAP-110 can remodel actin filaments in response to cellular signals modulated by Src and Pak, resulting in the formation of actin rosettes, lamellipodia and membrane ruffles.
The specific aims will determine (1) how AFAP-110 affects actin filament integrity, (2) whether disruption of actin filaments by AFAP-110 can affect cell morphology and motility, (3) how AFAP-110 is regulated and (4) how cellular signals from growth factors, SrC527F or Pak may effect the structure and function of AFAP-110. These data are both important and relevant to cancer, as AFAP-110 may directly modulate actin filament integrity in response to cellular signals known to effect cell morphology and motility, hallmarks of transformation and metastasis. AFAP-110 may also be a relevant therapeutic target and/or a molecular marker for prognosis, diagnosis and treatment of human cancers where cSrc is activated, e.g., breast and colon cancer.
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