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• W2024697792 abstract "The formation of extraembryonic endoderm is one of the earliest steps in the differentiation of pluripotent cells of the inner cell mass during the early stages of embryonic development. The primitive endoderm cells and the derived parietal and visceral endoderm cells gain the capacity to produce collagen IV and laminin. The deposition of these components results in the formation of basement membrane and epithelium of the endoderm, with polarized cells covering the inner surface of the blastocoels. We used retinoic acid-induced endoderm differentiation of stem cell-like F9 embryonic carcinoma cells to study the role of the Ras pathway and its regulation in the formation of the visceral endoderm. Upon endoderm differentiation of F9 cells induced by retinoic acid, c-Fos expression, the downstream target of the Ras pathway, is suppressed by uncoupling Elk-1 phosphorylation/activation to MAPK activity. However, attachment to matrix gel greatly enhances the activation of MAPK in endoderm cells but not in undifferentiated F9 cells. Enhanced MAPK activation as a result of contact with basement membrane is able to compensate for reduced Elk-1 phosphorylation and c-Fos expression. We conclude that endoderm differentiation renders the activation of the Ras pathway basement membrane dependent, contributing to the epithelial organization of the visceral endoderm. The formation of extraembryonic endoderm is one of the earliest steps in the differentiation of pluripotent cells of the inner cell mass during the early stages of embryonic development. The primitive endoderm cells and the derived parietal and visceral endoderm cells gain the capacity to produce collagen IV and laminin. The deposition of these components results in the formation of basement membrane and epithelium of the endoderm, with polarized cells covering the inner surface of the blastocoels. We used retinoic acid-induced endoderm differentiation of stem cell-like F9 embryonic carcinoma cells to study the role of the Ras pathway and its regulation in the formation of the visceral endoderm. Upon endoderm differentiation of F9 cells induced by retinoic acid, c-Fos expression, the downstream target of the Ras pathway, is suppressed by uncoupling Elk-1 phosphorylation/activation to MAPK activity. However, attachment to matrix gel greatly enhances the activation of MAPK in endoderm cells but not in undifferentiated F9 cells. Enhanced MAPK activation as a result of contact with basement membrane is able to compensate for reduced Elk-1 phosphorylation and c-Fos expression. We conclude that endoderm differentiation renders the activation of the Ras pathway basement membrane dependent, contributing to the epithelial organization of the visceral endoderm. In multicellular organisms, individual cells communicate with each other to maintain the harmony and homeostasis of the organism. One means of communication is through the release of soluble and diffusible factors such as hormones and growth factors, which bind the cell surface or nuclear receptors and trigger intracellular signaling. Direct physical contact mediated by cell surface receptors between cell-cell and cell-matrix are another kind of communication. The cell surface events transmit into the cell interior through cascades of biochemical reactions known as signal transduction, leading to modification of cellular enzymatic activities and gene expression. In the multicell structure, depending on the positioning cues provided by cell-cell and cell-matrix contacts, a particular cell type may differentially interpret the signal of a diffusible factor, leading to the modification of the intracellular signaling pathway and resulting in an integrated cellular response.The Ras/MAPK 1The abbreviations used are: MAPK/Erk, mitogen-activated protein kinase/extracellular-signal regulated kinase; MEK, MAPK/Erk kinase; Dab2, Disabled-2; E5, embryonic day 5; LRP, low density lipoprotein receptor-related protein; est, expressed sequence tag; MOPS, 4-morpholinepropanesulfonic acid; SPARC, secreted protein, acidic and rich in cysteine. 1The abbreviations used are: MAPK/Erk, mitogen-activated protein kinase/extracellular-signal regulated kinase; MEK, MAPK/Erk kinase; Dab2, Disabled-2; E5, embryonic day 5; LRP, low density lipoprotein receptor-related protein; est, expressed sequence tag; MOPS, 4-morpholinepropanesulfonic acid; SPARC, secreted protein, acidic and rich in cysteine. pathway is a major intracellular signaling pathway involved in cell proliferation, differentiation, and tumorigenicity (1Pawson T. Dev. Genet. 1993; 14: 333-338Google Scholar, 2Egan S.E. Weinberg R.A. Nature. 1993; 365: 781-783Google Scholar, 3Panaretto BA. J. Cell Sci. 1994; 107: 747-752Google Scholar). Investigation of mammalian cells in culture and model organisms have established the Ras/MAPK pathway; in responding to growth factor binding to cognate cell surface receptors, the small G protein, Ras, is activated by the exchange of bound GDP for GTP (2Egan S.E. Weinberg R.A. Nature. 1993; 365: 781-783Google Scholar, 3Panaretto BA. J. Cell Sci. 1994; 107: 747-752Google Scholar). Activated Ras binds and recruits Raf-1 to the cell surface. A cascade of kinases, Raf-1, MEK, and MAPK (or Erk), is sequentially phosphorylated and activated (4Johnson G.L. Vaillancourt R.R. Curr. Opin. Cell Biol. 1994; 6: 230-238Google Scholar, 5Whitmarsh A.J. Shore P. Sharrocks A.D. Davis R.J. Science. 1995; 269: 403-407Google Scholar, 6Robinson M.J. Cobb M.H. Curr. Opin. Cell Biol. 1997; 9: 180-186Google Scholar). Activated MAPK can then translocate into the nucleus to phosphorylate transcription factors to modulate gene expression. One common example is that MAPK phosphorylates and activates the transcription factor Elk-1 (7Yang S.H. Yates P.R. Whitmarsh A.J. Davis R.J. Sharrocks A.D. Mol. Cell. Biol. 1998; 18: 710-720Google Scholar, 8Yang S.H. Shore P. Willingham N. Lakey J.H. Sharrocks A.D. EMBO J. 1999; 18: 5666-5674Google Scholar, 9Cruzalegui F.H. Cano E. Treisman R. Oncogene. 1999; 18: 7948-7957Google Scholar). Subsequently, phosphorylated/activated Elk-1 binds the c-fospromoter and allows transcriptional activation of c-fos, an immediate early response gene (10Muller R. Bravo R. Burckhardt J. Curran T. Nature. 1984; 312: 716-720Google Scholar, 11Curran T. Bravo R. Muller R. Cancer Surv. 1985; 4: 655-681Google Scholar). Although it is not essential in gene knockout mice studies (12Wang Z.Q. Ovitt C. Grigoriadis A.E. Mohle-Steinlein U. Ruther U. Wagner E.F. Nature. 1992; 360: 741-745Google Scholar, 13Johnson R.S. Spiegelman B.M. Papaioannou V. Cell. 1992; 71: 577-586Google Scholar, 14Hu E. Mueller E. Oliviero S. Papaioannou V.E. Johnson R. Spiegelman B.M. EMBO J. 1994; 13: 3094-3103Google Scholar), c-Fos is thought to have an important role in cell cycle progression, cell differentiation, and tumorigenicity (15Brown J.R. Nigh E. Lee R.J., Ye, H. Thompson M.A. Saudou F. Pestell R.G. Greenberg M.E. Mol. Cell. Biol. 1998; 18: 5609-5619Google Scholar, 16Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Google Scholar, 17Holt J. Cancer Treat. Res. 1992; 63: 301-311Google Scholar, 18Saez E. Rutberg S.E. Mueller E. Oppenheim H. Smoluk J. Yuspa S.H. Spiegelman B.M. Cell. 1995; 82: 721-732Google Scholar, 19Arteaga C.L. Holt J.T. Cancer Res. 1996; 56: 1098-1103Google Scholar).The effects of cell-cell and cell-matrix contacts have been recognized and analyzed in cell culture (22Renshaw M.W. Ren X.D. Schwartz M.A. EMBO J. 1997; 16: 5592-5599Google Scholar, 23Schlaepfer D.D. Hunter T. Cell Struct. Funct. 1996; 21: 445-450Google Scholar, 24Howe A.K. Aplin A.E. Juliano R.L. Curr. Opin. Genet. Dev. 2002; 12: 30-35Google Scholar, 25Lin T.H. Aplin A.E. Shen Y. Chen Q. Schaller M. Romer L. Aukhil I. Juliano R.L. J. Cell Biol. 1997; 136: 1385-1395Google Scholar). In epithelia, the cells are often organized by a sheet of basement membrane composed of a scaffold composed mainly of collagen IV and laminin (27Timpl R. Dziadek M. Int. Rev. Exp. Pathol. 1986; 29: 1-112Google Scholar, 28Martin G.R. Rohrbach D.H. Terranova V.P. Liotta L.A. Monogr. Pathol. 1983; 24: 16-30Google Scholar, 29Adams J.C. Watt F.M. Development. 1993; 117: 1183-1198Google Scholar). The cells located in the stroma are in contact with an extracellular matrix composed of proteins such as fibronectin, collagen I, collagen III, etc. (26Couchman J.R. Austria M.R. Woods A. J. Invest. Dermatol. 1990; 94 (suppl.): 7S-14SGoogle Scholar). It has been found that NIH3T3 fibroblasts attached to a fibronectin substratum, compared with cells in suspension, are much more efficient in transmitting the Ras/MAPK signal (20Chen Q. Kinch M.S. Lin T.H. Burridge K. Juliano R.L. J. Biol. Chem. 1994; 269: 26602-26605Google Scholar, 21Lin T.H. Chen Q. Howe A. Juliano R.L. J. Biol. Chem. 1997; 272: 8849-8852Google Scholar, 22Renshaw M.W. Ren X.D. Schwartz M.A. EMBO J. 1997; 16: 5592-5599Google Scholar, 23Schlaepfer D.D. Hunter T. Cell Struct. Funct. 1996; 21: 445-450Google Scholar, 24Howe A.K. Aplin A.E. Juliano R.L. Curr. Opin. Genet. Dev. 2002; 12: 30-35Google Scholar, 25Lin T.H. Aplin A.E. Shen Y. Chen Q. Schaller M. Romer L. Aukhil I. Juliano R.L. J. Cell Biol. 1997; 136: 1385-1395Google Scholar). The regulated step in cell attachment is the activation of Raf-1 by Ras, because tyrosine phosphorylation and Ras activation are not affected, and Raf-1, MEK, and MAPK activation are much stronger in adherent than in suspended cells (21Lin T.H. Chen Q. Howe A. Juliano R.L. J. Biol. Chem. 1997; 272: 8849-8852Google Scholar, 22Renshaw M.W. Ren X.D. Schwartz M.A. EMBO J. 1997; 16: 5592-5599Google Scholar).Thus far, most of the cell culture studies of cell-matrix interaction on signaling have used fibroblasts as models (20Chen Q. Kinch M.S. Lin T.H. Burridge K. Juliano R.L. J. Biol. Chem. 1994; 269: 26602-26605Google Scholar, 21Lin T.H. Chen Q. Howe A. Juliano R.L. J. Biol. Chem. 1997; 272: 8849-8852Google Scholar, 22Renshaw M.W. Ren X.D. Schwartz M.A. EMBO J. 1997; 16: 5592-5599Google Scholar, 23Schlaepfer D.D. Hunter T. Cell Struct. Funct. 1996; 21: 445-450Google Scholar, 24Howe A.K. Aplin A.E. Juliano R.L. Curr. Opin. Genet. Dev. 2002; 12: 30-35Google Scholar, 25Lin T.H. Aplin A.E. Shen Y. Chen Q. Schaller M. Romer L. Aukhil I. Juliano R.L. J. Cell Biol. 1997; 136: 1385-1395Google Scholar). However, the profound effects of basement membrane contact on growth, death, and differentiation of epithelial cells have been recognized (27Timpl R. Dziadek M. Int. Rev. Exp. Pathol. 1986; 29: 1-112Google Scholar, 28Martin G.R. Rohrbach D.H. Terranova V.P. Liotta L.A. Monogr. Pathol. 1983; 24: 16-30Google Scholar, 29Adams J.C. Watt F.M. Development. 1993; 117: 1183-1198Google Scholar, 30Ingber D.E. Madri J.A. Jamieson J.D. Am. J. Pathol. 1986; 122: 129-139Google Scholar, 31Bissell M.J. Barcellos-Hoff M.H. J. Cell Sci. 1987; 8: 327-343Google Scholar). The presence and intactness of basement membrane are dynamically regulated by altering synthesis and degradation and have important roles in development (28Martin G.R. Rohrbach D.H. Terranova V.P. Liotta L.A. Monogr. Pathol. 1983; 24: 16-30Google Scholar, 29Adams J.C. Watt F.M. Development. 1993; 117: 1183-1198Google Scholar) and in physiological processes such as mammary gland involution (32Talhouk R.S. Bissell M.J. Werb Z. J. Cell Biol. 1992; 118: 1271-1282Google Scholar, 33Martinez-Hernandez A. Fink L.M. Pierce G.B. Lab. Invest. 1976; 34: 455-462Google Scholar), and ovarian surface rupture during ovulation (34Talbot P. Martin G.G. Ashby H. Gamete Res. 1987; 17: 287-302Google Scholar, 35Okamura H. Fukumoto M. Mori T. Adv. Prostaglandin Thromboxane Leukotriene Res. 1985; 15: 597-599Google Scholar, 36Dennefors B. Tjugum J. Norstrom A. Janson P.O. Nilsson L. Hamberger L. Wilhelmsson L. Prostaglandins. 1982; 24: 295-302Google Scholar, 37Beers W.H. Strickland S. Reich E. Cell. 1975; 6: 387-394Google Scholar). Analysis of cell-basement membrane contact on cellular signaling is lacking, probably because of the lack of proper models for epithelial cells and basement membrane in cultures. Most of the established cell lines of epithelial origin have not been able to faithfully mimic the in vivo properties of interaction with basement membrane because they have already undergone changes to become independent of the basement membrane during the process of adapting to tissue culture conditions (38Capo-chichi C.D. Smith E.R. Yang D.H. Roland I.H. Vanderveer L. Cohen C. Hamilton T.C. Godwin A.K. Xu X.X. Cancer. 2002; (in press)Google Scholar).Here, we used the F9 embryonic carcinoma cells as a model to investigate the Ras/MAPK signaling pathway and its regulation by basement membrane. F9 cells are a well characterized teratocarcinoma line derived from tumors of the gonads (testes). F9 cells are undifferentiated, with characteristics resembling those of stem cells in early embryos, and have been widely used to study early embryonic development and retinoic acid regulation (39Gajovic S. Chowdhury K. Gruss P. Exp. Cell Res. 1998; 242: 138-143Google Scholar, 40Sherman M.I. Miller R.A. Dev. Biol. 1978; 63: 27-34Google Scholar, 41Grover A. Adamson E.D. Dev. Biol. 1986; 114: 492-503Google Scholar, 42Mason I. Murphy D. Hogan B.L. Differentiation. 1985; 30: 76-81Google Scholar, 43Faria T.N. LaRosa G.J. Wilen E. Liao J. Gudas L.J. Mol. Cell. Endocrinol. 1998; 143: 155-166Google Scholar, 44Faria T.N. Mendelsohn C. Chambon P. Gudas L.J. J. Biol. Chem. 1999; 274: 26783-26788Google Scholar, 45Cho S.Y. Cho S.Y. Lee S.H. Park S.S. Mol. Cell. 1999; 30: 179-184Google Scholar). Induced by retinoic acid, F9 cells undergo differentiation into visceral endoderm cells, an epithelial cell type in the early embryo (40Sherman M.I. Miller R.A. Dev. Biol. 1978; 63: 27-34Google Scholar, 41Grover A. Adamson E.D. Dev. Biol. 1986; 114: 492-503Google Scholar). We found that, accompanying epithelial differentiation of the F9 cells, the regulation of the Ras/MAPK pathway is altered (46Smith E.R. Smedberg J.L. Rula M.E. Hamilton T.C. Xu X.X. J. Biol. Chem. 2001; 276: 32094-32100Google Scholar, 47Smith E.R. Capo-Chichi C.D., He, J. Smedberg J.L. Yang D.H. Prowse A.H. Godwin A.K. Hamilton T.C. Xu X.X. J. Biol. Chem. 2001; 276: 47303-47310Google Scholar); the activation of MAPK and Elk-1 is uncoupled, and MAPK activation is enhanced by contact with basement membrane to compensate for the inefficiency in Elk-1 activation and c-Fos expression. Thus, the Ras/MAPK pathway is altered in F9 cell differentiation so that the cells become basement membrane-dependent.DISCUSSIONThe retinoic acid-induced differentiation of F9 embryonic carcinoma cells from stromal cells of the inner cell mass to visceral endoderm cells with epithelial properties, can be used as a model for the analysis of epithelium-basement membrane interaction. It is anticipated that cellular signaling would be modified as a result of altered gene expression during F9 cell differentiation. Retinoic acid induces the expression of laminin, collagen IV, and Dab2 (Fig.8). The promoter of the laminin gene contains retinoic acid responsive element (52Vasios G.W. Gold J.D. Petkovich M. Chambon P. Gudas L.J. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 9099-9103Google Scholar) and may be induced directly by retinoic acid. GATA-4 and GATA-6 factors induced in embryonic stem cells and embryonic carcinoma cells mediate the expression of collagen IV and Dab2 (50Morrisey E.E. Musco S. Chen M.Y., Lu, M.M. Leiden J.M. Parmacek M.S. J. Biol. Chem. 2000; 275: 19949-19954Google Scholar).In this study, we found that the regulation of Ras/MAPK is altered when F9 cells undergo retinoic acid-induced visceral endoderm differentiation (Fig. 8). Elk-1 phosphorylation and c-Fos expression are uncoupled from MAPK activation, which is mediated by Dab2 in differentiated cells (46Smith E.R. Smedberg J.L. Rula M.E. Hamilton T.C. Xu X.X. J. Biol. Chem. 2001; 276: 32094-32100Google Scholar, 47Smith E.R. Capo-Chichi C.D., He, J. Smedberg J.L. Yang D.H. Prowse A.H. Godwin A.K. Hamilton T.C. Xu X.X. J. Biol. Chem. 2001; 276: 47303-47310Google Scholar). Conversely, differentiation of F9 cells results in sensitization of MAPK activation to serum stimulation when the cells are in contact with basement membranes mimicked by Matrigel (Fig. 8). The property of basement membrane contact in enhanced MAPK activation is unique for differentiated, epithelium-like F9 cells and is not present in undifferentiated F9 cells. The combination of these two separate differentiation-associated alterations results in the activation of c-Fos expression, the downstream target of Ras/MAPK pathway, to become basement membrane-dependent. As a result, following visceral endoderm differentiation, the serum- and growth factor-activated Ras/MAPK/Elk-1/c-Fos pathway and cell growth depend on attachment to basement membrane (Fig. 8). Therefore, the Ras/MAPK pathway acts to ensure the growth advantage of epithelial cells attached to the basement membrane, contributing to the organization of visceral endoderm epithelium along a sheet of basement membrane.Presumably, Dab2 expression contributes to the growth-suppressive activity of retinoic acid in F9 cells in culture by suppressing c-Fos expression, disassociated from MAPK activation. Dab2 can suppress c-Fos expression in other epithelial cell types besides endoderm cells (53He J. Smith E.R. Xu X.X. J. Biol. Chem. 2001; 276: 26814-26818Google Scholar). Uncoupling of MAPK activation and c-Fos expression was observed in other scenarios such as the expression of α-synuclein (54Iwata A. Miura S. Kanazawa I. Sawada M. Nukina N. J. Neurochem. 2001; 77: 239-252Google Scholar), KSR (kinase suppressor of Ras) (55Sugimoto T. Stewart S. Han M. Guan K.L. EMBO J. 1998; 17: 1717-1727Google Scholar, 56Sugimoto T. Stewart S. Guan K.L. J. Biol. Chem. 1997; 272: 29415-29418Google Scholar), and Gab2 (57Zhao C., Yu, D.H. Shen R. Feng G.S. J. Biol. Chem. 1999; 274: 19649-19654Google Scholar). The mechanism for the uncoupling of MAPK activation and Elk-1 phosphorylation by Dab2 is not yet clear. Cellular endocytic trafficking is likely to play a role in transporting and regulating the convergence and disassociation of the kinase MAPK and the substrate Elk-1, first because Dab2 is known to associate with megalin (58Oleinikov A.V. Zhao J. Makker S.P. Biochem. J. 2000; 347: 613-621Google Scholar) and myosin VI (59Morris S.M. Arden S.D. Roberts R.C. Kendrick-Jones J. Cooper J.A. Luzio J.P. Buss F. Traffic. 2002; 3: 331-341Google Scholar,60Inoue A. Sato O. Homma K. Ikebe M. Biochem. Biophys. Res. Commun. 2002; 292: 300-307Google Scholar), and additionally, all three proteins, Dab2 (61Morris S.M. Cooper J.A. Traffic. 2001; 2: 111-123Google Scholar), megalin (62Howell B.W. Herz J. Curr. Opin. Neurobiol. 2001; 11: 74-81Google Scholar), and myosin VI (63Buss F. Luzio J.P. Kendrick-Jones J. FEBS Lett. 2001; 508: 295-299Google Scholar), are thought to participate in the endocytic transport of membrane vesicles and attached signaling molecules (including MAPK and Elk-1). Furthermore, endocytosis and cellular trafficking, are known to regulate cellular signaling (64Verhey K.J. Meyer D. Deehan R. Blenis J. Schnapp B.J. Rapoport T.A. Margolis B. J. Cell Biol. 2001; 152: 959-970Google Scholar, 65Goldstein L.S. Science. 2001; 291: 2102-2103Google Scholar).The mechanism for the effect of basement membrane contact on MAPK activation presumably involves integrins. The engagement of integrin is known to activate the Ras/MAPK pathway in NIH3T3 fibroblasts (20Chen Q. Kinch M.S. Lin T.H. Burridge K. Juliano R.L. J. Biol. Chem. 1994; 269: 26602-26605Google Scholar, 24Howe A.K. Aplin A.E. Juliano R.L. Curr. Opin. Genet. Dev. 2002; 12: 30-35Google Scholar,25Lin T.H. Aplin A.E. Shen Y. Chen Q. Schaller M. Romer L. Aukhil I. Juliano R.L. J. Cell Biol. 1997; 136: 1385-1395Google Scholar). In fibroblasts, attachment of the cells to a surface, as opposed to suspension, is sufficient for MAPK activation (20Chen Q. Kinch M.S. Lin T.H. Burridge K. Juliano R.L. J. Biol. Chem. 1994; 269: 26602-26605Google Scholar, 21Lin T.H. Chen Q. Howe A. Juliano R.L. J. Biol. Chem. 1997; 272: 8849-8852Google Scholar, 22Renshaw M.W. Ren X.D. Schwartz M.A. EMBO J. 1997; 16: 5592-5599Google Scholar, 23Schlaepfer D.D. Hunter T. Cell Struct. Funct. 1996; 21: 445-450Google Scholar, 24Howe A.K. Aplin A.E. Juliano R.L. Curr. Opin. Genet. Dev. 2002; 12: 30-35Google Scholar, 25Lin T.H. Aplin A.E. Shen Y. Chen Q. Schaller M. Romer L. Aukhil I. Juliano R.L. J. Cell Biol. 1997; 136: 1385-1395Google Scholar). Unlike fibroblasts, differentiated F9 cells appear to require contact with an intact basement membrane, rather than with just the surface or individual components of the basement membrane, to enhance MAPK activation. Possibly, the collaboration between subtypes of integrins specific for binding to collagen IV and laminin mediates the MAPK activation. Alternatively, other basement membrane-binding cell surface receptors such as megalin and LRP may be involved. We found that the activity to enhance MAPK activation can be mimicked by Matrigel but not by individual or a combination of purified components, including collagen IV, laminin, and fibronectin. It is possible that other minor basement membrane component(s) such as SPARC in Matrigel contributes to the activity in enhancing MAPK activation. Alternatively, the mixing of purified individual components in vivo is not able to mimic fully the biochemical structure; hence the activity of the basement membrane. Matrigel preparation, on the other hand, may be able to preserve basement membrane properties constituted by the components thereof.The uncoupling of c-Fos expression from MAPK activation is mediated by Dab2 in both visceral endoderm cells (46Smith E.R. Smedberg J.L. Rula M.E. Hamilton T.C. Xu X.X. J. Biol. Chem. 2001; 276: 32094-32100Google Scholar, 47Smith E.R. Capo-Chichi C.D., He, J. Smedberg J.L. Yang D.H. Prowse A.H. Godwin A.K. Hamilton T.C. Xu X.X. J. Biol. Chem. 2001; 276: 47303-47310Google Scholar) and other epithelial cells of adult tissues such as breast (53He J. Smith E.R. Xu X.X. J. Biol. Chem. 2001; 276: 26814-26818Google Scholar) and ovary (66Sheng Z. Sun W. Smith E. Cohen C. Sheng Z. Xu X.X. Oncogene. 2000; 19: 4847-4854Google Scholar). Thus, it is likely that the role of Dab2 regulation of the Ras/MAPK pathway in epithelial organization is not unique to visceral endoderm cells but is common to other epithelial cells. Dab2 is often lost in epithelial tumor cells (67Mok S.C. Chan W.Y. Wong K.K. Cheung K.K. Lau C.C., Ng, S.W. Baldini A. Colitti C.V. Rock C.O. Berkowitz R.S. Oncogene. 1998; 16: 2381-2387Google Scholar, 68Fazili Z. Sun W. Mittelstaedt S. Cohen C. Xu X.X. Oncogene. 1999; 18: 3104-3113Google Scholar), and its loss correlates with the transformation of the epithelial cells to become basement membrane-independent and disorganized (66Sheng Z. Sun W. Smith E. Cohen C. Sheng Z. Xu X.X. Oncogene. 2000; 19: 4847-4854Google Scholar, 69Yang D.H. Smith E.R. Cohen C. Patriotis C. Godwin A.K. Hamilton T.C. Xu X.X. Cancer. 2002; 94: 2380-2392Google Scholar). Previously, Dab2 has been proposed to function in epithelial cell positional organization (51Yang D.H. Smith E.R. Roland I.H. Sheng Z. He J. Martin W.D. Hamilton T.C. Lambeth J.D. Xu X.X. Dev. Biol. 2002; (in press)Google Scholar, 66Sheng Z. Sun W. Smith E. Cohen C. Sheng Z. Xu X.X. Oncogene. 2000; 19: 4847-4854Google Scholar). The current conclusion that Ras/MAPK signaling is basement membrane-dependent provides a mechanism for the role of Dab2 in epithelial cell positional organization and underlines the critical role of Dab2 expression loss in the epithelial cell transformation to become basement membrane-independent in tumorigenicity. In multicellular organisms, individual cells communicate with each other to maintain the harmony and homeostasis of the organism. One means of communication is through the release of soluble and diffusible factors such as hormones and growth factors, which bind the cell surface or nuclear receptors and trigger intracellular signaling. Direct physical contact mediated by cell surface receptors between cell-cell and cell-matrix are another kind of communication. The cell surface events transmit into the cell interior through cascades of biochemical reactions known as signal transduction, leading to modification of cellular enzymatic activities and gene expression. In the multicell structure, depending on the positioning cues provided by cell-cell and cell-matrix contacts, a particular cell type may differentially interpret the signal of a diffusible factor, leading to the modification of the intracellular signaling pathway and resulting in an integrated cellular response. The Ras/MAPK 1The abbreviations used are: MAPK/Erk, mitogen-activated protein kinase/extracellular-signal regulated kinase; MEK, MAPK/Erk kinase; Dab2, Disabled-2; E5, embryonic day 5; LRP, low density lipoprotein receptor-related protein; est, expressed sequence tag; MOPS, 4-morpholinepropanesulfonic acid; SPARC, secreted protein, acidic and rich in cysteine. 1The abbreviations used are: MAPK/Erk, mitogen-activated protein kinase/extracellular-signal regulated kinase; MEK, MAPK/Erk kinase; Dab2, Disabled-2; E5, embryonic day 5; LRP, low density lipoprotein receptor-related protein; est, expressed sequence tag; MOPS, 4-morpholinepropanesulfonic acid; SPARC, secreted protein, acidic and rich in cysteine. pathway is a major intracellular signaling pathway involved in cell proliferation, differentiation, and tumorigenicity (1Pawson T. Dev. Genet. 1993; 14: 333-338Google Scholar, 2Egan S.E. Weinberg R.A. Nature. 1993; 365: 781-783Google Scholar, 3Panaretto BA. J. Cell Sci. 1994; 107: 747-752Google Scholar). Investigation of mammalian cells in culture and model organisms have established the Ras/MAPK pathway; in responding to growth factor binding to cognate cell surface receptors, the small G protein, Ras, is activated by the exchange of bound GDP for GTP (2Egan S.E. Weinberg R.A. Nature. 1993; 365: 781-783Google Scholar, 3Panaretto BA. J. Cell Sci. 1994; 107: 747-752Google Scholar). Activated Ras binds and recruits Raf-1 to the cell surface. A cascade of kinases, Raf-1, MEK, and MAPK (or Erk), is sequentially phosphorylated and activated (4Johnson G.L. Vaillancourt R.R. Curr. Opin. Cell Biol. 1994; 6: 230-238Google Scholar, 5Whitmarsh A.J. Shore P. Sharrocks A.D. Davis R.J. Science. 1995; 269: 403-407Google Scholar, 6Robinson M.J. Cobb M.H. Curr. Opin. Cell Biol. 1997; 9: 180-186Google Scholar). Activated MAPK can then translocate into the nucleus to phosphorylate transcription factors to modulate gene expression. One common example is that MAPK phosphorylates and activates the transcription factor Elk-1 (7Yang S.H. Yates P.R. Whitmarsh A.J. Davis R.J. Sharrocks A.D. Mol. Cell. Biol. 1998; 18: 710-720Google Scholar, 8Yang S.H. Shore P. Willingham N. Lakey J.H. Sharrocks A.D. EMBO J. 1999; 18: 5666-5674Google Scholar, 9Cruzalegui F.H. Cano E. Treisman R. Oncogene. 1999; 18: 7948-7957Google Scholar). Subsequently, phosphorylated/activated Elk-1 binds the c-fospromoter and allows transcriptional activation of c-fos, an immediate early response gene (10Muller R. Bravo R. Burckhardt J. Curran T. Nature. 1984; 312: 716-720Google Scholar, 11Curran T. Bravo R. Muller R. Cancer Surv. 1985; 4: 655-681Google Scholar). Although it is not essential in gene knockout mice studies (12Wang Z.Q. Ovitt C. Grigoriadis A.E. Mohle-Steinlein U. Ruther U. Wagner E.F. Nature. 1992; 360: 741-745Google Scholar, 13Johnson R.S. Spiegelman B.M. Papaioannou V. Cell. 1992; 71: 577-586Google Scholar, 14Hu E. Mueller E. 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It has been found that NIH3T3 fibroblasts attached to a fibronectin substratum, compared with cells in suspension, are much more efficient in transmitting the Ras/MAPK signal (20Chen Q. Kinch M.S. Lin T.H. Burridge K. Juliano R.L. J. Biol. Chem. 1994; 269: 26602-26605Google Scholar, 21Lin T.H. Chen Q. Howe A. Juliano R.L. J. Biol. Chem. 1997; 272: 8849-8852Google Scholar, 22Renshaw M.W. Ren X.D. Schwartz M.A. EMBO J. 199" @default.
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