Department of Biology, Duke University, Durham, NC 27708-0338, USA.
J Cell Sci. 2010 Jul 1;123(Pt 13):2179-89. doi: 10.1242/jcs.067868. Epub 2010 Jun 1.
Wg/Wnt signals specify cell fates in both invertebrate and vertebrate embryos and maintain stem-cell populations in many adult tissues. Deregulation of the Wnt pathway can transform cells to a proliferative fate, leading to cancer. We have discovered that two Drosophila proteins that are crucial for cytokinesis have a second, largely independent, role in restricting activity of the Wnt pathway. The fly homolog of RacGAP1, Tumbleweed (Tum)/RacGAP50C, and its binding partner, the kinesin-like protein Pavarotti (Pav), negatively regulate Wnt activity in fly embryos and in cultured mammalian cells. Unlike many known regulators of the Wnt pathway, these molecules do not affect stabilization of Arm/beta-catenin (betacat), the principal effector molecule in Wnt signal transduction. Rather, they appear to act downstream of betacat stabilization to control target-gene transcription. Both Tum and Pav accumulate in the nuclei of interphase cells, a location that is spatially distinct from their cleavage-furrow localization during cytokinesis. We show that this nuclear localization is essential for their role in Wnt regulation. Thus, we have identified two modulators of the Wnt pathway that have shared functions in cell division, which hints at a possible link between cytokinesis and Wnt activity during tumorigenesis.
Wg/Wnt 信号在无脊椎动物和脊椎动物胚胎中指定细胞命运，并在许多成年组织中维持干细胞群体。Wnt 途径的失调会使细胞向增殖命运转化，导致癌症。我们发现，两种对胞质分裂至关重要的果蝇蛋白在限制 Wnt 途径活性方面具有第二个、很大程度上独立的作用。RacGAP1 的果蝇同源物 Tumbleweed（Tum）/RacGAP50C 及其结合伴侣，类驱动蛋白蛋白 Pavarotti（Pav），在果蝇胚胎和培养的哺乳动物细胞中负调节 Wnt 活性。与许多已知的 Wnt 途径调节剂不同，这些分子不影响 Arm/beta-catenin（betacat）的稳定，betacat 是 Wnt 信号转导中的主要效应分子。相反，它们似乎在 betacat 稳定化的下游作用，以控制靶基因转录。Tum 和 Pav 都在有丝分裂细胞的核内积累，这一位置与它们在胞质分裂过程中的分裂沟定位在空间上是不同的。我们表明，这种核定位对于它们在 Wnt 调节中的作用是必不可少的。因此，我们已经确定了两个 Wnt 途径调节剂，它们在细胞分裂中具有共同的功能，这暗示了细胞分裂和肿瘤发生过程中 Wnt 活性之间可能存在联系。
