Mirjam Zegers, Ph.D.

Regulation of epithelial morphogenesis

The research in my laboratory focuses primarily on the question of how the extracellular environment of epithelial cells regulates its morphogenesis.   It is well known that interactions of cells with the underlying matrix or with neighboring cells profoundly affect cellular morphology and that sites of cell-cell or cell-matrix interactions are important signaling nodes. My research interests center on the question of how cell-cell and cell-matrix-mediated activation of Rho GTPase effector molecules affect epithelial morphogenesis.

We currently focus on the role of the p21-activated kinase 1 (Pak1), a serine/threonine kinase activated downstream of the Rho GTPase Rac.  Pak1 activity is upregulated in a wide variety of carcinoma cells and we previously reported that inhibition of Pak function in normal epithelial cells abolished the ability of cells to undergo contact inhibition of proliferation.  We hypothesize that these mutants interfere with contact inhibition by failing to translocate a Pak-containing signaling complex from cell-matrix to cell-cell contacts.  We are investigating the regulation of this protein complex and aim to define how this complex regulates cellular signaling at either site.

A second project involves the role of Pak1 in cell polarization and lumen formation.  Using a 3-dimensional culture system of MDCK cells grown in a collagen matrix, we previously reported that Rac acts downstream of integrins in the regulation of basement membrane formation, which in turn regulates cell polarization and lumen formation.  We currently investigate the potential role of Pak1 as a downstream effector for the Rac-mediated effects on morphogenesis.

Yu, W, Datta, A., Leroy, P., O'Brien, L.E., Mak, G., Jou, T-S., Matlin, K., Mostov, K.E., Zegers, M.M.P., ß1-integrin orients epithelial polarity via Rac1 and laminin. Mol. Biol. Cell., 16, 433-455, 2005.

Zegers, M.M.P., Forget M.A., Chernoff, J, Mostov, K.E., ter Beest, M.B.A., Hansen, S.H., Pak1 and PIX regulate contact inhibition during epithelial wound healing. EMBO J., 22, 4155-4166, 2003.

Mostov, K. and Zegers, M., Just mix and patch. Nature, 422, 267-268, 2003.

Zegers, M.M.P., O'Brien, L.E., Datta, A., Yu, W. and Mostov, K.E., Epithelial polarity and tubulogenesis in vitro. Trends Cell Biol., 13, 169-176, 2003.

Yu, W, O'Brien, L.E., Wang, F., Bourne, H., Mostov, H., Zegers, M.M.P., Hepatocyte growth factor switches orientation of polarity and mode of movement during morphogenesis of multicellular epithelial structures. Mol. Biol. Cell., 14, 748-763, 2003.

O'Brien, L.E., Zegers, M.M.P., Mostov, K.E., Building epithelial achitecture: insights from three-dimensional culture models.  Nature Rev. Mol. Cell Biol., 3, 531- 537, 2002.

Hansen, S.H., Zegers, M.M.P., Woodrow, M., Rodriquez-Viciana, P., Chardin, P., Mostov, K.E., McMahon, M., Induced expression of Rnd3 is associated with transformation of polarized epithelial cells by the Raf-MEK-Extracellular signal-regulated pathway. Mol. Cell Biol., 20, 9364-9375, 2000.

Zegers, M.M.P., Zaal, K.J.M., Hoekstra, D., Functional involvement of proteins, interacting with sphingolipids, in sphingolipid transport to the bile canalicular membrane of the human hepatocytic cell line HepG2. Hepatology 27,1089-1097, 1998.

Zegers, M.M.P., Zaal, K.J.M., van IJzendoorn, S.C.D., Klappe, K., Hoekstra, D., Actin filaments and micotubules are involved in different membrane traffic pathways that transport sphingolipids to the apical surface of polarized HepG2 cells. Mol. Biol. Cell, 9, 1349-1359, 1998.

Zegers, M.M.P. and Hoeksta, D., Mechanisms and functional aspects of polarized membrane traffic in epithelial and hepatic cells. Biochem.J., 336, 257-269, 1998.