Asymmetric mitosis: Unequal segregation of proteins destined for degradation

Abstract

Mitotic cell division ensures that two daughter somatic cells inherit identical genetic material. Previous work has shown that signaling by the Smad1 transcription factor is terminated by polyubiquitinylation and proteasomal degradation after essential phosphorylations by MAPK and glycogen synthase kinase 3 (GSK3). Here, we show that, unexpectedly, proteins specifically targeted for proteasomal degradation are inherited preferentially by one mitotic daughter during somatic cell division. Experiments with dividing human embryonic stem cells and other mammalian cultured cell lines demonstrated that in many supposedly equal mitoses the segregation of proteins destined for degradation (Smad1 phosphorylated by MAPK and GSK3, phospho-␤-catenin, and total polyubiquitinylated proteins) was asymmetric. Transport of pSmad1 targeted for degradation to the centrosome required functional microtubules. In vivo, an antibody specific for Mad phosphorylated by MAPK showed that this antigen was associated preferentially with one of the two centrosomes in Drosophila embryos at cellular blastoderm stage. We propose that this remarkable cellular property may be explained by the asymmetric inheritance of peripheral centrosomal proteins when centrioles separate and migrate to opposite poles of the cell, so that one mitotic daughter remains pristine. We conclude that many mitotic divisions are unequal, unlike what was previously thought. Since the description of mitosis by Flemming in 1882, studies on somatic cell division have focused on the equal partition of cellular materials, in particular that of the chromosomes and mitotic apparatus, between cell daughters (1, 2). We now report that many mitotic divisions are unequal with respect to pericentrosomal proteins targeted for proteasomal degradation. The starting point for this investigation was provided by recent work showing that the duration of the Smad1 signal triggered by bone morphogenetic proteins (BMPs) is controlled by an elaborate protein degradation pathway (Fig. 1A). After activation via C-terminal phosphorylation by BMP receptor (BMPR), Smad1 is subjected to sequential phosphorylations by MAPK and glycogen synthase kinase 3 (GSK3) in its linker (middle) region. The MAPK and GSK3 phosphorylations are both required for the polyubiquitinylation and degradation of Smad1 (Fig. 1 A) (3, 4). We developed potent phospho-specific antibodies for positions Ser-214 (pSmad1 MAPK ) and Ser-210 (pSmad1 GSK3 ) that allow one to follow the intracellular location of Smad1 protein that has been specifically targeted for degradation (4).As is well known, centrosomes ensure that cells divide equally at mitosis and contain small centriole doublets surrounded by a matrix of proteins such as ␥-tubulin and pericentrin that serve as the microtubule-organizing center (MTOC) (2). In recent years, the realization has emerged that the centrosome also functions as the proteolytic center of the cell. The key to this discovery was the finding that cultured mammalian cells treated with proteasome inhibit...

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