Lgr6 Marks Stem Cells in the Hair Follicle That Generate All Cell Lineages of the Skin.pdf

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Lgr6 Marks Stem Cells in the Hair Follicle That Generate All Cell Lineages of the Skin.pdf

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Lgr6 Marks Stem Cells in the Hair Follicle That Generate All Cell Lineages of the Skin

One of the proteins identified through this screen was CD44, a cell membrane-bound glyco- protein involved in cell adhesion and migration (38). The spatial organization of CD44 upon ephrin-A1 stimulation was found to antilocalize with the assembly of EphA2 (Fig. 4D), validat- ing the involvement of CD44 in cell-driven EphA2 receptor reorganization. The system- wide correlation analysis does not necessarily provide the mechanistic details leading to EphA2 sorting; instead, it identifies proteins and genes that may serve as surrogate markers to centripetal transport. In conclusion, we report a spatio-mechanical regulation of the EphA2 signaling pathway. Upon membrane-bound ligand stimulation, EphA2 is transported radially inwards by an actomyosin contractile process. Physical interference with this transport, which necessarily involves the imposition of opposing forces on EphA2, alters ligand-induced EphA2 activation as observed by the recruitment of the protease ADAM10 and cytoskeleton morphology. Quantitative mea- surement of centripetal receptor transport across a library of mammary epithelial cell lines re- veals a high correlation with invasion potential and with specific gene and protein expression. These observations suggest that spatio-mechanical aspects of ephrin-A1 expressing cells and their surrounding tissue environment may functionally alter the response of EphA2 signaling systems and could play a contributing role in the onset and progression of cancer. References and Notes 1. D. E. Discher, P. Janmey, Y.-l. Wang, Science 310, 1139 (2005). 2. M. J. Dalby et al., Nat. Mater. 6, 997 (2007). 3. C. M. Nelson, M. M. VanDuijn, J. L. Inman, D. A. Fletcher, M. J. Bissell, Science 314, 298 (2006). 4. D. T. Butcher, T. Alliston, V. M. Weaver, Nat. Rev. Cancer 9, 108 (2009). 5. C. S. Chen, J. Cell Sci. 121, 3285 (2008). 6. S. Y. Qi, J. T. Groves, A. K. Chakraborty, Proc. Natl. Acad. Sci. U.S.A. 98, 6548 (2001). 7. K. D. Mossman, G. Campi, J. T. Groves, M. L. Dustin