Abstract
Thus, in spite of widely divergent developmental mechanisms, worms and flies both use a member of the PAR-1/MARK/KIN1 family during an early step in polarity establishment. What does this mean? One possibility is that this is a case of a conserved function being independently co-opted by evolution for use in polarity. That is, conserved features of this family of kinases (e.g., a regulatable kinase activity and a C-terminal domain with a hypothetical role in localization) have been selected independently for a role in polarity during evolution of the two animals. In this case, the method of activation, the substrates, and the output would be expected to be different. The more interesting possibility, however, is that this family of kinases is part of a biochemical pathway that has been conserved for its role in setting polarity in a variety of organisms and cell types. If so, then we clearly have much to learn about this new pathway in both systems.Several observations are consistent with co-option. First is the failure to identify other conserved components after extensive genetic analysis in each system. Second is the difference in the apparent output of kinase activity. Although Drosophila PAR-1 seems to most directly affect microtubule organization, there is no evidence that C. elegans PAR-1 affects microtubule organization. In fact, most aspects of C. elegans polarity are resistant to microtubule-inhibiting drugs and sensitive to microfilament-inhibiting drugs. Third, although PAR-1 localization depends upon PAR-3, the PAR-3 homolog, Bazooka (see below), does not have a role in localizing Drosophila PAR-1. Similarly, although Drosophila PAR-1 localization depends upon oskar, there is no recognizable oskar homolog in worms.On the other hand, none of these observations rule out conservation of a core cassette of interacting proteins with a fundamental role in polarity. It is possible that the direct activators and targets of PAR-1/MARK/KIN1 family members are conserved but have fundamental roles throughout development and therefore, like Drosophila PAR-1, will only be discovered by reverse genetic methods. In addition, the output of PAR-1 in the two systems may not be as different as it appears; the role of microtubules in C. elegans polarity is still an open question. Other observations more positively support a conserved cassette. Conservation of PAR-1 fits well with the apparent conservation of function of germline granules in flies and worms. Perhaps most compelling is the consistent coincidence of PAR-1/MARK/KIN1 family kinases with polarity systems in other organisms and cell types. KIN1 has a clear role in polarity in yeast and Drosophila PAR-1, in addition to its polar distribution in oocytes, is restricted basolaterally in follicle cells, a distribution that has also been seen for mammalian PAR-1 in polarized epithelial cells (see Shulman et al. 2000xShulman, J.M, Benton, R, and St Johnston, D. Cell. 2000; 101: 377–388Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesShulman et al. 2000).Possible conservation of PAR function in polarity is not limited to PAR-1. Homologs of PAR-3 have been identified and are associated with polarity in flies and in mammals. A PAR-3 homolog in Drosophila, Bazooka, has recently been found to be localized apically in embryonic epithelial cells, is required for maintenance of the epithelium, and plays a key role in cell polarity during the asymmetric divisions of neuroblasts (See Jan and Jan 2000xJan, Y.-N and Jan, L.Y. Cell. 2000; 100: 599–602Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesJan and Jan 2000). Although the function of mammalian PAR-3 is not clearly known, it is also localized apically in epithelial cells and like PAR-3, biochemically interacts with an atypical protein kinase C (Izumi et al. 1998xIzumi, Y, Hirose, T, Tamai, Y, Hirai, S, Nagashima, Y, Fujimoto, T, Tabuse, Y, Kemphues, K, and Ohno, S. J. Cell Biol. 1998; 143: 95–106Crossref | PubMed | Scopus (375)See all ReferencesIzumi et al. 1998).Although the extent to which PAR function is conserved between animals remains to be seen, it seems pretty clear that PARs are polar and that understanding the function of this interesting class of proteins promises to yield insights into establishment of polarity in a wide range of systems.*E-mail: kjk1@cornell.edu
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