Rac Activation upon Cell-Cell Contact Formation Is Dependent on Signaling from the Epidermal Growth Factor Receptor

Abstract

Cadherins are transmembrane receptors that mediate cell-cell adhesion. They play an essential role in embryonic development and maintenance of tissue architecture. The Rho family small GTPases regulate actin cytoskeletal dynamics in different cell types. The function of two family members, Rho and Rac, is required for the stability of cadherins at cell-cell contacts. Consistent with the published data we have found that Rac is activated upon induction of intercellular adhesion in epithelial cells. This activation is dependent on functional cadherins (Nakagawa, M., Fukata, M., Yamaga, M., Itoh, N., and Kaibuchi, K. (2001) J. Cell Sci. 114, 1829–1838; Noren, N. K., Niessen, C. M., Gumbiner, B. M., and Burridge, K. (2001) J. Biol. Chem. 276, 3305–3308). Here we show for the first time that clustering of cadherins using antibody-coated beads is sufficient to promote Rac activation. In the presence of Latrunculin B, Rac can be partially activated by antibody-clustered cadherins. These results suggest that actin polymerization is not required for initial Rac activation. Contrary to what has been described before, phosphatidylinositol 3-kinases are not involved in Rac activation following cell-cell adhesion in keratinocytes. Interestingly, inhibition of epidermal growth factor receptor signaling efficiently blocks the increased Rac-GTP levels observed after contact formation. We conclude that cadherin-dependent adhesion can activate Rac via epidermal growth factor receptor signaling. Cadherins are transmembrane receptors that mediate cell-cell adhesion. They play an essential role in embryonic development and maintenance of tissue architecture. The Rho family small GTPases regulate actin cytoskeletal dynamics in different cell types. The function of two family members, Rho and Rac, is required for the stability of cadherins at cell-cell contacts. Consistent with the published data we have found that Rac is activated upon induction of intercellular adhesion in epithelial cells. This activation is dependent on functional cadherins (Nakagawa, M., Fukata, M., Yamaga, M., Itoh, N., and Kaibuchi, K. (2001) J. Cell Sci. 114, 1829–1838; Noren, N. K., Niessen, C. M., Gumbiner, B. M., and Burridge, K. (2001) J. Biol. Chem. 276, 3305–3308). Here we show for the first time that clustering of cadherins using antibody-coated beads is sufficient to promote Rac activation. In the presence of Latrunculin B, Rac can be partially activated by antibody-clustered cadherins. These results suggest that actin polymerization is not required for initial Rac activation. Contrary to what has been described before, phosphatidylinositol 3-kinases are not involved in Rac activation following cell-cell adhesion in keratinocytes. Interestingly, inhibition of epidermal growth factor receptor signaling efficiently blocks the increased Rac-GTP levels observed after contact formation. We conclude that cadherin-dependent adhesion can activate Rac via epidermal growth factor receptor signaling. lysophosphatidic acid extracellular signal-regulated kinase epidermal growth factor phosphatidylinositol 3-kinase guanine nucleotide exchange factor Ccd42/Rac interactive binding p21-activated kinase GTPase activating protein mitogen-activated protein kinase/ERK kinase bovine serum albumin vascular endothelial Cadherins are transmembrane receptors that mediate calcium-dependent cell-cell adhesion. They play an essential role in embryonic development and maintenance of tissue architecture in adults (1Gumbiner B.M. Cell. 1996; 84: 345-357Abstract Full Text Full Text PDF PubMed Scopus (2977) Google Scholar). Cadherins interact in an anti-parallel fashion with the same type of receptors on adjacent cells (known as homophilic binding), thereby mediating formation of cell-cell contacts. Intercellular adhesion is strengthened by the clustering of cadherin receptors at junctions and the association between cadherin complexes and the actin cytoskeleton (2Adams C.L. Nelson W.J. Curr. Opin. Cell Biol. 1998; 10: 572-577Crossref PubMed Scopus (238) Google Scholar, 3Yap A.S. Brieher W.M. Gumbiner B.M. Ann. Rev. Cell Dev. Biol. 1997; 13: 119-146Crossref PubMed Scopus (690) Google Scholar). Cadherin-dependent adhesion is subject to regulation by cytoplasmic proteins, and recent work has focused on modulation by the Rho family of small GTPases. Members of this family of GTP-binding proteins regulate actin cytoskeletal dynamics and focal complex formation in different cell types (4Hall A. Science. 1998; 279: 509-514Crossref PubMed Scopus (5271) Google Scholar). The function of two family members, Rho and Rac, is required for the stability of cadherins at cell-cell contacts (5Braga V. Exp. Cell Res. 2000; 261: 83-90Crossref PubMed Scopus (108) Google Scholar). The exact mechanisms by which Rho and Rac operate are unclear, but we and others have shown that Rac plays a role in actin recruitment to junctions (6Takaishi K. Sasaki T. Kotani H. Nishioka H. Takai Y. J. Cell Biol. 1997; 139: 1047-1059Crossref PubMed Scopus (475) Google Scholar) and to clustered cadherin receptors (7Braga V.M.M. Machesky L.M. Hall A. Hotchin N.A. J. Cell Biol. 1997; 137: 1421-1431Crossref PubMed Scopus (661) Google Scholar, 8Lambert M. Choquet D. Mege R.-M. J. Cell Biol. 2002; 157: 469-479Crossref PubMed Scopus (110) Google Scholar). Rho and Rac function in signal transduction cascades downstream of a variety of cell surface receptors. For example, Rho mediates stress fiber formation in response to lysophosphatidic acid (LPA)1 stimulation, whereas Rac is required for growth factor-induced membrane ruffling (9Kjoller L. Hall A. Exp. Cell Res. 1999; 253: 166-179Crossref PubMed Scopus (344) Google Scholar). More recently it has been directly demonstrated that ligand binding to cell surface receptors can activate Rho and Rac (10Ren X.D. Kiosses W.B. Schwartz M.A. EMBO J. 1999; 18: 578-585Crossref PubMed Scopus (1374) Google Scholar, 11Bernard V. Bohl B. Bokoch G. J. Biol. Chem. 1999; 274: 13196-13204Abstract Full Text Full Text PDF Scopus (84) Google Scholar). In addition, the regulation of the activity of Rho, Rac, and Cdc42 by integrin engagement has been determined and shown to be dependent on time, matrix composition, and matrix concentration (12Adams J.C. Schwartz M.A. J. Cell Biol. 2000; 150: 807-822Crossref PubMed Scopus (107) Google Scholar, 13del Pozo M.A. Price L.S. Alderson N.B. Ren X.D. Schwartz M.A. EMBO J. 2000; 19: 2008-2014Crossref PubMed Scopus (405) Google Scholar, 14Cox E.A. Sastry S.K. Huttenlocher A. Mol. Biol. Cell. 2001; 12: 265-277Crossref PubMed Scopus (252) Google Scholar, 15Wenk M.B. Midwood K.S. Schwarzbauer J.E. J. Cell Biol. 2000; 150: 913-919Crossref PubMed Scopus (108) Google Scholar). Lately, it has become apparent that cadherin-mediated adhesion can trigger intracellular signaling events including activation of phosphatidylinositol 3-kinases (PI3-kinases) and the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway (16Kim S.H., Li, Z. Sacks D.B. J. Biol. Chem. 2000; 275: 36999-37005Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 17Pece S. Chiariello M. Murga C. Gutkind J.S. J. Biol. Chem. 1999; 274: 19347-19351Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 18Pece S. Gutkind J.S. J. Biol. Chem. 2000; 275: 41227-41233Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). In addition, the epidermal growth factor (EGF) receptor has been coimmunoprecipitated with the cadherin adhesion complex from epithelial cells and is activated upon cell-cell contact formation (18Pece S. Gutkind J.S. J. Biol. Chem. 2000; 275: 41227-41233Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 19Hoschuetzky H. Aberle H. Kemler R. J. Cell Biol. 1994; 127: 1375-1380Crossref PubMed Scopus (675) Google Scholar). Furthermore, recent work has demonstrated that cell-cell contact formation can activate Rac in Madine-Darby canine kidney and Chinese hamster ovary cells transfected with C-cadherin (20Nakagawa M. Fukata M. Yamaga M. Itoh N. Kaibuchi K. J. Cell Sci. 2001; 114: 1829-1838Crossref PubMed Google Scholar,21Noren N.K. Niessen C.M. Gumbiner B.M. Burridge K. J. Biol. Chem. 2001; 276: 3305-3308Abstract Full Text Full Text PDF Scopus (357) Google Scholar). Spreading of E-cadherin-expressing Chinese hamster ovary cells on immobilized E-cadherin ectodomain also induces Rac activation (22Kovacs E.M. Ali R.G. McCormack A.J. Yap A.S. J. Biol. Chem. 2002; 277: 6708-6718Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). In addition, levels of GTP-bound Rac are higher in VE-cadherin-expressing endothelial cells than in VE-cadherin-null cells (23Lampugnani M.G. Zanetti A. Breviario F. Balconi G. Orsenigo F. Corada M. Spagnuolo R. Betson M. Braga V. Dejana E. Mol. Biol. Cell. 2002; 13: 1174-1189Crossref Scopus (206) Google Scholar). Although these studies showed that Rac activation is dependent on cadherin function, they did not establish the functional significance of Rac activation upon cell-cell contact formation, nor did they address the question of whether cadherin clustering is sufficient to enhance GTP loading on Rac. Although two studies found that PI3-kinase activity was required for full Rac activation, inhibition of PI3-kinase function did not reduce Rac activity to basal levels (20Nakagawa M. Fukata M. Yamaga M. Itoh N. Kaibuchi K. J. Cell Sci. 2001; 114: 1829-1838Crossref PubMed Google Scholar, 22Kovacs E.M. Ali R.G. McCormack A.J. Yap A.S. J. Biol. Chem. 2002; 277: 6708-6718Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar), suggesting that other signaling pathways may be involved in Rac activation downstream of cadherin-mediated adhesion. In light of these results, we were interested to determine whether cadherin-mediated adhesion could also activate Rac in keratinocytes. Normal keratinocytes provide the ideal system to look at Rac activation on induction of cell-cell adhesion. They can be grown to confluence in the absence of cadherin-dependent contacts (in and cell-cell adhesion can be by of (known as the J. Cell Biol. 1994; PubMed Scopus Google Scholar). cells are and they not to to and contact formation this we the for Rac activation following cell-cell contact formation in of clustering of cadherin actin and PI3-kinase and receptor signaling. results light on the mechanisms via which cadherin receptors are to Rac activation. Normal keratinocytes and were as described Betson M., Li, N. Mol. Biol. Cell. 2000; PubMed Scopus Google Scholar). were grown to confluence in Betson M., Li, N. Mol. Biol. Cell. 2000; PubMed Scopus Google Scholar). intercellular adhesion was to and protein were as described (7Braga V.M.M. Machesky L.M. Hall A. Hotchin N.A. J. Cell Biol. 1997; 137: 1421-1431Crossref PubMed Scopus (661) Google Scholar). was as described (7Braga V.M.M. Machesky L.M. Hall A. Hotchin N.A. J. Cell Biol. 1997; 137: 1421-1431Crossref PubMed Scopus (661) Google Scholar). and Y. A. S. M. Google Y. T. M. Y. S. J. Cell Biol. PubMed Scopus Google R. D. C. L. J. Cell Biol. PubMed Scopus Google receptor from and from V.M.M. Cell PubMed Scopus Google J. Curr. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google receptor E. B. N. J. 2000; PubMed Scopus Google receptor and and were from and were from using a were as described S. T. F. J. Cell Biol. 1998; PubMed Scopus Google Scholar). of keratinocytes was data were in and and were with beads for and beads were with and proteins and of were by and for Rac. For cells were with and for at to of a cells were with For clustering keratinocytes grown in were for on with and was to and cells were for at For beads were with described as (7Braga V.M.M. Machesky L.M. Hall A. Hotchin N.A. J. Cell Biol. 1997; 137: 1421-1431Crossref PubMed Scopus (661) Google Scholar). Latrunculin was to which actin cytoskeleton in keratinocytes were with Latrunculin for and with beads beads for In inhibition cells were with (18Pece S. Gutkind J.S. J. Biol. Chem. 2000; 275: 41227-41233Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar), for to with for In cells were with as described with for for cells were in and were by and using for on J. Curr. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). were in and were on and for activated receptor receptor on E. B. N. J. 2000; PubMed Scopus Google Scholar). of studies have shown that a of Rac the of cadherin receptors at of cell-cell contact (6Takaishi K. Sasaki T. Kotani H. Nishioka H. Takai Y. J. Cell Biol. 1997; 139: 1047-1059Crossref PubMed Scopus (475) Google Scholar, V.M.M. Machesky L.M. Hall A. Hotchin N.A. J. Cell Biol. 1997; 137: 1421-1431Crossref PubMed Scopus (661) Google Scholar). are to function by for the small the guanine nucleotide exchange in Cell. Biol. 1999; PubMed Scopus Google Scholar). to be than for Rho family of which are in exchange activity in Y. Sci. 2002; Full Text Full Text PDF Scopus Google Scholar). it is that blocks cadherin-mediated adhesion by inhibition of a Rho GTPase other than Rac. determine whether Rac play a role in regulation of cadherin at intercellular we whether an activated of Rac can the of on cell-cell contacts. Normal keratinocytes in the absence of intercellular contacts were with Rac and cell-cell adhesion was for were and for E-cadherin and (7Braga V.M.M. Machesky L.M. Hall A. Hotchin N.A. J. Cell Biol. 1997; 137: 1421-1431Crossref PubMed Scopus (661) Google Scholar), of cadherin receptors at between cells of on cadherin at junctions after for and Interestingly, of and the of on cadherin-mediated adhesion and This is for cadherin in cells. K. these results provide that blocks of cadherin receptors at junctions by Rac Rac plays an role in the regulation of cadherin-mediated adhesion. Rac activity is required for the stability of cadherin receptors at is Rac activated upon cell-cell contact formation in Rac activation, we the interactive binding of the Rac p21-activated kinase S. T. F. J. Cell Biol. 1998; PubMed Scopus Google Scholar). We the of the by loading with and Rac activity whether cell-cell adhesion can activate the small GTPase Rac, we keratinocytes in and cell-cell contacts for time Rac activation. We found that Rac was activated of of and this activation was to and is that the of Rac described was by of calcium-dependent intracellular signaling pathways than induction of cadherin-dependent adhesion. between these two we cadherin function the at two of the cadherin family and Y. A. S. M. Google Scholar). were with and at to cadherin function in keratinocytes J. Cell Biol. 1994; PubMed Scopus Google Scholar). that the cadherin function, we demonstrated in the presence of the cadherin clustering was found at intercellular with Rac upon of whereas did not the Rac activation is dependent on functional cadherin and of is not sufficient to trigger Rac activation. These results demonstrated that cell-cell adhesion by cadherins could activate Rac in keratinocytes. formation is by the clustering of cadherin receptors A.S. Brieher W.M. Gumbiner B.M. Ann. Rev. Cell Dev. Biol. 1997; 13: 119-146Crossref PubMed Scopus (690) Google Scholar), we whether clustering of cadherins with was sufficient to activate Rac. grown in were with and of the receptors was by of for Rac these we could of cadherins on the cell surface by We found that clustering a in Rac activity to the were of the Rac activation in that of cells with a in Rac activation to cells with of surface cadherins with two of a in Rac activation and the of Rac activation after clustering is than the activation observed following cell-cell contact formation We that this Rac activation may be to the small of cadherin this we cells for in with beads with of cells with these beads binding of beads to the cell surface and recruitment of and to the beads In beads with to the cell and that did We found that cells with beads showed increased Rac activation in with cells with beads of the results of that beads Rac activation by a factor of with beads suggesting that clustering of cadherins is sufficient to activate Rac. determine whether actin polymerization is required for Rac activation by clustered cadherin we cells with Latrunculin to receptor Latrunculin actin polymerization by actin M. PubMed Scopus (661) Google Scholar, D. Y. Cell 13: PubMed Scopus Google Scholar). of cells with Latrunculin for beads binding of beads to the cell surface and recruitment of but actin recruitment for Rac activation, we found that Latrunculin an in Rac activation. with E-cadherin beads in the presence of Latrunculin a in Rac activation Rac activation can in the absence actin but full induction of Rac activity formation of actin the of beads to cadherin receptors may the Rac activity is for E. Hall A. Science. 1998; PubMed Scopus Google Scholar). the that beads may Rac activation by events in a to that this was not the we cells with beads with cell surface these beads showed for but did beads did not increased Rac activity to beads the clustering of cadherin receptors can activate Rac. We which signaling pathways operate downstream of cadherin-dependent contact formation to Rac We different of signaling the and We of the and of the and mitogen-activated kinase J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, A. A. Science. PubMed Scopus Google Scholar, A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We that the were functional by for on activated and and activation of these were of keratinocytes with increased Rac activity with but did not Rac activation by cell-cell adhesion. We that not play a role in Rac activation downstream of cadherin adhesion in keratinocytes. to of keratinocytes with increased Rac activity the Rac activation upon induction of cell-cell adhesion. we that receptor function in cadherin-dependent Rac Consistent with this cell-cell adhesion induces receptor activation in keratinocytes E. and V. M. M. as has been observed in cells (18Pece S. Gutkind J.S. J. Biol. Chem. 2000; 275: 41227-41233Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). Rac activation in these was to the with was in the of Rac activation by For this Rac activity was also to the with and was at The Latrunculin B, can activate Rac in keratinocytes. whether this Rac activation is a of with different we cells with the with did not the basal of Rac activity in nor did it activation of Rac by cell-cell contact formation of these is shown in and signaling pathways in not to Rac activation. In addition, these results that the kinase is not involved in induction of GTP loading on Rac downstream of cadherin-dependent adhesion. activation of Rac is in A.J. C.L. D. Hall A. Cell. Full Text PDF PubMed Scopus Google Scholar). results, we were interested to determine whether a pathway in keratinocytes. grown in the absence of cell-cell contacts were with the PI3-kinase and with for in cells induces a Rac activation, this is by inhibition of PI3-kinase as in Rac activation is in keratinocytes. results for the first time that activated Rac can the of a Rac on the of cadherin receptors at cell-cell contact This is for activated Rac and be by activated that Rac plays a role in the regulation of intercellular junctions in keratinocytes. work has shown that Rac for the of Rho function in cadherin-mediated adhesion and epithelial (7Braga V.M.M. Machesky L.M. Hall A. Hotchin N.A. J. Cell Biol. 1997; 137: 1421-1431Crossref PubMed Scopus (661) Google Scholar, Nelson W.J. J. Cell Biol. 1998; PubMed Scopus Google Scholar). results that Rho, Rac, and Cdc42 have formation in keratinocytes. We have shown that induction of cell-cell adhesion in keratinocytes an of Rac This increased Rac activation is by inhibition of cadherin function, with published data (20Nakagawa M. Fukata M. Yamaga M. Itoh N. Kaibuchi K. J. Cell Sci. 2001; 114: 1829-1838Crossref PubMed Google Scholar, N.K. Niessen C.M. Gumbiner B.M. Burridge K. J. Biol. Chem. 2001; 276: 3305-3308Abstract Full Text Full Text PDF Scopus (357) Google Scholar). we have demonstrated that clustering of cadherins using antibody-coated is sufficient to GTP loading on Rac. This response is to clustering of cadherins and is not upon clustering of in keratinocytes. We have shown that Rac plays a role in actin recruitment to clustered E-cadherin receptors (7Braga V.M.M. Machesky L.M. Hall A. Hotchin N.A. J. Cell Biol. 1997; 137: 1421-1431Crossref PubMed Scopus (661) Google Scholar). we for the first time that Rac activation can of full induction of GTP loading on Rac formation of actin of cadherin receptors are with actin in the absence of cell-cell adhesion Y. N. S. M. A. J. Cell Biol. 1998; PubMed Scopus Google Scholar). clustering of this of receptors provide a for actin Rac activation actin recruitment and thereby cadherin receptors at In the of these we observed that of keratinocytes with two that the actin Latrunculin and induces Rac activation and data not actin but they by different mechanisms M. PubMed Scopus (661) Google Scholar, D. Y. Cell 13: PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). Interestingly, has also been shown to activate Rho (10Ren X.D. Kiosses W.B. Schwartz M.A. EMBO J. 1999; 18: 578-585Crossref PubMed Scopus (1374) Google Scholar). In addition, that the have been shown to Rho and Rac activity (10Ren X.D. Kiosses W.B. Schwartz M.A. EMBO J. 1999; 18: 578-585Crossref PubMed Scopus (1374) Google Scholar, C.M. Burridge K. Cell. 1999; PubMed Scopus Google Scholar). the activity of Rho family GTPases to be to the polymerization of and is that proteins as and GTPase activating proteins at cytoskeletal and that upon of the they may be to Rho and Rac V. M. M. Curr. Opin. Cell in to what is observed with of actin inhibition of and the receptor increased the basal levels of Rac activation. This was not a of cells with of signaling the which blocks activation, did not enhance Rac Although these results are the mechanisms via which these may with activation of Rho proteins are the of this can clustering of cadherin receptors promote Rac address this question we which signaling pathways be In to the work of (20Nakagawa M. Fukata M. Yamaga M. Itoh N. Kaibuchi K. J. Cell Sci. 2001; 114: 1829-1838Crossref PubMed Google Scholar), we have found that Rac activation following cell-cell contact formation is not dependent on PI3-kinase results are with in which initial Rac activation following adhesion of E-cadherin-expressing Chinese hamster ovary cells to E-cadherin ectodomain is (22Kovacs E.M. Ali R.G. McCormack A.J. Yap A.S. J. Biol. Chem. 2002; 277: 6708-6718Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). in which Rac activation of PI3-kinase activity is in N. S. L. 1999; PubMed Google Scholar). In we have demonstrated that receptor signaling in the of Rac activity in keratinocytes upon formation. of receptor signaling blocks Rac activation and at time after induction of cell-cell Consistent with in keratinocytes cell-cell adhesion the and receptor is to cadherin clustered by work that receptor signaling is also required for increased GTP loading on Rac by clustering of cadherin on data are in with the that cadherin clustering to receptor recruitment and activation at cell-cell contact (18Pece S. Gutkind J.S. J. Biol. Chem. 2000; 275: 41227-41233Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 19Hoschuetzky H. Aberle H. Kemler R. J. Cell Biol. 1994; 127: 1375-1380Crossref PubMed Scopus (675) Google Scholar). to other cell Rac activation is in keratinocytes. This that Rac activation by two different on the receptor is activated by clustering with cadherins by ligand In of this is in the suggesting that the of receptor activation may on the ligand and the of the receptor in the cell D.B. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. E.A. J. 1996; Full Text PDF PubMed Scopus Google Scholar, K. S.K. J. 1999; 276: PubMed Google Scholar). on the that Rac function cadherin receptors at junctions (7Braga V.M.M. Machesky L.M. Hall A. Hotchin N.A. J. Cell Biol. 1997; 137: 1421-1431Crossref PubMed Scopus (661) Google Scholar) and results, we that the receptor with of cell-cell contacts. the inhibition of receptor signaling not of cadherins at junctions upon of were in Madine-Darby canine kidney PI3-kinase inhibition Rac activation, it did not formation recruitment of to junctions (20Nakagawa M. Fukata M. Yamaga M. Itoh N. Kaibuchi K. J. Cell Sci. 2001; 114: 1829-1838Crossref PubMed Google Scholar). for these is that the Rac activation, it is that the results not in Rac activity at cell-cell contacts. receptor inhibition may an increased of GTP on Rac, in GTP-bound Rac is observed R. D. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). be Rac activity is required for the of cell-cell contacts than cadherin clustering M. M. and Rac function of actin recruitment to clustered cadherin receptors (7Braga V.M.M. Machesky L.M. Hall A. Hotchin N.A. J. Cell Biol. 1997; 137: 1421-1431Crossref PubMed Scopus (661) Google Scholar), suggesting that pathways also to actin polymerization at is which can promote actin at cell-cell contact and is activated upon intercellular formation in cells (16Kim S.H., Li, Z. Sacks D.B. J. Biol. Chem. 2000; 275: 36999-37005Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, A. K. K. Nishioka H. Takai Y. 1999; 18: PubMed Scopus Google Scholar). pathways may also be including signaling and V. C. M. E. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, K.S. V. A. J. Cell Sci. 2001; 114: PubMed Google Scholar). These pathways may for the in Rac activation by receptor basal levels of activated Rac are for cell-cell contacts inhibition of Rac activity cadherin-mediated adhesion (7Braga V.M.M. Machesky L.M. Hall A. Hotchin N.A. J. Cell Biol. 1997; 137: 1421-1431Crossref PubMed Scopus (661) Google Scholar). Rac activation not play a role in cadherin at which other signaling events Rac activation recent results suggest that receptor signaling is is in actin recruitment to junctions formation of other as We that the Rac activation may play a role in other cadherin-dependent of growth of are required to this The between receptor activation and the in GTP loading in Rac is is to activation of a GTP loading on inhibition of a GTP mechanisms in an in the levels of is in to the for Rac activation formation in keratinocytes. is for the of a between cadherin-mediated adhesion and growth factor signaling. For example, cadherin receptors with receptor V. C. L. B. E. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), whereas with in endothelial cells M.G. L. Breviario F. V. F. Balconi G. Spagnuolo R. B. M. Zanetti A. A. V. D. E. F. A. R. F. D. Dejana E. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The between cadherins and growth factor receptors may be to the observed between and growth factor which cell and E. Science. 1999; PubMed Scopus Google Scholar). This may also to the in cadherin signaling in different cells on the growth factor receptor that is to with the cadherin Here we in the first of between growth and small GTPases. In cadherin receptor clustering is sufficient to activate Rac, and cadherin-dependent Rac activation receptor signaling. The functional of the Rac activation are at the the regulation of epithelial and events in which cadherin Rac, and receptor signaling have been (1Gumbiner B.M. Cell. 1996; 84: 345-357Abstract Full Text Full Text PDF PubMed Scopus (2977) Google Scholar, V. Exp. Cell Res. 2000; 261: 83-90Crossref PubMed Scopus (108) Google Scholar, Curr. Opin. Cell Biol. 1999; PubMed Scopus Google Scholar). work is to determine which of these are by the between cadherin receptors and signaling We L. and C. for We also M. D. S. J. and H. for J. for the and A. S. and J. for