Adenomatous polyposis coli (APC)-mediated actin nucleation is required for directed cell migration

M.Angeles Juanes, Richa Jaiswal, Ali Badache, BL Goode

    Research output: Contribution to journalMeeting Abstract

    Abstract

    Adenomatous polyposis coli (APC) is a tumor suppressor protein with important roles in Wnt signaling as
    well as cytoskeletal rearrangements that govern cell migration, cell protrusion, and cell adhesion.
    Because APC is a large multi‐domain protein with a wide spectrum of activities and cellular binding
    partners, it has been difficult to pinpoint which of these activities and interactions are important for its
    different in vivo functions. To address this, we generated a separation‐of‐function allele in APC that
    specifically disrupts its actin nucleation activity, a function that until now has only been studied in vitro.
    Our previous studies showed that a C‐terminal 78 kDa fragment of APC (2130‐2843), which includes the
    ‘basic domain’, interacts with actin monomers, nucleates actin assembly, and directly collaborates with
    formins via a ‘rocket launcher’ mechanism to promote actin assembly. Here, we mapped the nucleation
    activity to specific residues in the basic domain, and found that mutations at this site disrupt the ability
    of APC to stimulate actin nucleation in vitro, both alone and in collaboration with formins. Importantly,
    this mutation had no effect on APC’s ability to bind or bundle microtubules. In U2OS cells, silencing of
    endogenous APC led to a striking loss of microtubule and mitochondria staining at the cell cortex, and a
    pronounced defect in directed cell migration. Expression of an RNAi‐refractive wild‐type full‐length APC
    rescued all of these defects. However, full‐length mutant APC only rescued the microtubule and
    mitochondria defects, and not the cell migration defects. Thus, our results indicate that APC’s actin
    nucleation activity is required for its functions in directed cell migration, but not MT capture/stability or
    mitochondria transport. These findings also raise the intriguing possibility that APC‐mediated actin
    nucleation facilitates the migration of colonic crypt epithelial cells, and thus contributes to its role as a
    tumor suppressor.
    Original languageEnglish
    Article numberM216
    Pages (from-to)59
    JournalMolecular Biology of the Cell
    Volume27
    Publication statusPublished - 2016

    Bibliographical note

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156534/bin/supp_27_25_3947__index.html

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