Research ArticleCell Biology

The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division

See allHide authors and affiliations

Sci. Signal.  02 Jan 2018:
Vol. 11, Issue 511, eaam8705
DOI: 10.1126/scisignal.aam8705

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Lipid modification promotes cancer cell heterogeneity

Asymmetric cell division generates daughter cells that have distinct fates and is accomplished through the unequal distribution of cell fate determinants or signaling pathway components. Stypulkowski et al. found that the depalmitoylase APT1 was asymmetrically localized in dividing cancer cells, and its catalytic activity was required for asymmetric localization of the Notch antagonist Numb and the Wnt signaling mediator β-catenin, both of which are palmitoylated. The polarity complex component CDC42 was required for the asymmetric localization of both APT1 and β-catenin. APT1-mediated asymmetric partitioning of Numb and β-catenin restricted Notch and Wnt signaling to one daughter cell or the other, induced a mammary stem cell transcriptional signature in breast cancer cells, and promoted heterogeneity and self-renewal capacity in breast cancer cells. These results identify palmitoylation-dependent asymmetric partitioning of cell fate determinants as a potential driver of tumor cell heterogeneity, which has been associated with tumor progression and metastatic potential.

Abstract

Asymmetric cell division results in two distinctly fated daughter cells. A molecular hallmark of asymmetric division is the unequal partitioning of cell fate determinants. We have previously established that growth factor signaling promotes protein depalmitoylation to foster polarized protein localization, which, in turn, drives migration and metastasis. We report protein palmitoylation as a key mechanism for the asymmetric partitioning of the cell fate determinants Numb and β-catenin through the activity of the depalmitoylating enzyme APT1. Using point mutations, we showed that specific palmitoylated residues on Numb were required for its asymmetric localization. By live-cell imaging, we showed that reciprocal interactions between APT1 and the Rho family GTPase CDC42 promoted the asymmetric localization of Numb and β-catenin to the plasma membrane. This, in turn, restricted Notch- or Wnt-responsive transcriptional activity to one daughter cell. Moreover, we showed that altering APT1 abundance changed the transcriptional signatures of MDA-MB-231 triple receptor–negative breast cancer cells, similar to changes in Notch and β-catenin–mediated Wnt signaling. We also showed that loss of APT1 depleted a specific subpopulation of tumorigenic cells in colony formation assays. Together, our findings suggest that APT1-mediated depalmitoylation is a major mechanism of asymmetric cell division that maintains Notch- and Wnt-associated protein dynamics, gene expression, and cellular functions.

View Full Text