Chromosome movements during mitosis are orchestrated primarily by the interaction of spindle microtubules with the kinetochore, the site for attachment of spindle microtubules to the centromere. Kinetochore‐associated mitotic kinesin CENP‐E plays key roles in chromosome congression and spindle checkpoint satisfaction. We have recently identified and characterized syntelin, a novel selective CENP‐E inhibitor (Ding et al., 2010. Cell Res. 20, 1386‐1390). Cells treated with syntelin progress through interphase, enter mitosis normally with a bipolar spindle and lagging chromosomes around the poles. Syntelin is an allosteric inhibitor which tightens CENP‐E‐microtubule interaction by slowing inorganic phosphate release. To delineate the role of CENP‐E in reorganization of interpolar microtubules into an organized central spindle, metaphase synchronized cells were exposed to syntelin and other mitotic motor inhibitors. Syntelin does not perturb interpolar microtubule assembly but abrogates the anti‐parallel microtubule bundle formation. Real‐time image shows that CENP‐E inhibited cells undergo central spindle splitting and exhibits chromosome instability phenotypes. Interestingly, inhibition of CENP‐E did not alter the interaction between CENP‐E and PRC1 but perturbed temporal assembly of PRC1 to the midzone. Surprisingly, inhibition of CENP‐E perturbs the temporal control of PRC1 dephosphorylation which led to a persistent phosphorylation of PRC1 and an inhibition of central spindle assembly. These findings reveal a previously uncharacterized role of CENP‐E motor in temporal control of central spindle assembly. Grant Funding Source: DK56292; CA164133
Tumor metastasis represents the main causes of cancer-related death. Our recent study showed that chemokine CCL18 secreted from tumor-associated macrophages regulates breast tumor metastasis, but the underlying mechanisms remain less clear. Here, we show that ARF6 GTPase-activating protein ACAP4 regulates CCL18-elicited breast cancer cell migration via the acetyltransferase PCAF-mediated acetylation. CCL18 stimulation elicited breast cancer cell migration and invasion via PCAF-dependent acetylation. ACAP4 physically interacts with PCAF and is a cognate substrate of PCAF during CCL18 stimulation. The acetylation site of ACAP4 by PCAF was mapped to Lys311 by mass spectrometric analyses. Importantly, dynamic acetylation of ACAP4 is essential for CCL18-induced breast cancer cell migration and invasion, as overexpression of the persistent acetylation-mimicking or non-acetylatable ACAP4 mutant blocked CCL18-elicited cell migration and invasion. Mechanistically, the acetylation of ACAP4 at Lys311 reduced the lipid-binding activity of ACAP4 to ensure a robust and dynamic cycling of ARF6–ACAP4 complex with plasma membrane in response to CCL18 stimulation. Thus, these results present a previously undefined mechanism by which CCL18-elicited acetylation of the PH domain controls dynamic interaction between ACAP4 and plasma membrane during breast cancer cell migration and invasion.
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