Inhibition of Invasion of Epithelial Cells by Tiam1-Rac Signaling

Hordijk, Peter L.; Klooster, Jean Paul ten; Kammen, Rob A. van der; Michiels, Frits; Oomen, L. C. J. M.; Collard, John G.

doi:10.1126/science.278.5342.1464

Cited by 415 publications

(366 citation statements)

References 23 publications

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“…In breast tumor cells, such as SP-1 cells, Tiam1 is detected as a 200-kD protein (Fig. 1), which is similar to the Tiam1 described in other cell types (Woods and Bryant 1991; Michiels et al 1995; Nobes and Hall 1995; Van Leeuwen et al 1995, Van Leeuwen et al 1997; Hordijk et al 1997; Stam et al 1997; Bourguignon et al 2000). Tiam1, isolated from SP-1 cells, is also capable of carrying out GDP/GTP exchange for Rac1 in vitro (Fig.…”

Section: Discussionsupporting

confidence: 64%

“…Rac1 acts downstream of Tiam1 signaling and regulates the function of several cell adhesion molecules such as the laminin receptor, α6β1 integrin (Van Leeuwen et al 1997), E-cadherin (Hordijk et al 1997), and the hyaluronan receptor, CD44 (Bourguignon et al 2000). Tiam1-Rac1 activation also has been shown to be stimulated by certain serum-derived growth activators (e.g., S1P and LPA) during T-lymphoma cell invasion (Stam et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Tiam1-Rac1 activation also has been shown to be stimulated by certain serum-derived growth activators (e.g., S1P and LPA) during T-lymphoma cell invasion (Stam et al 1998). However, in epithelial MDCK cells, Tiam1-Rac1 signaling plays an invasion/suppressor role in Ras-transformed MDCK cells (Hordijk et al 1997). Apparently, various responses by Tiam1-catalyzed Rac1 signaling may be controlled by selective upstream activators (e.g., availability of certain cytoskeletal proteins [e.g., ankyrin], cell adhesion receptors [e.g., CD44, integrin or E-cadherin], growth activators [e.g., serum, S1P, or LPA] or extracellular matrix components [hyaluronic acid, collagen, or fibronectin, etc.]).…”

Section: Discussionmentioning

confidence: 99%

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Ankyrin–Tiam1 Interaction Promotes Rac1 Signaling and Metastatic Breast Tumor Cell Invasion and Migration

Bourguignon

Zhu

Shao

et al. 2000

The Journal of Cell Biology

116

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Tiam1 (T-lymphoma invasion and metastasis 1) is one of the known guanine nucleotide (GDP/GTP) exchange factors (GEFs) for Rho GTPases (e.g., Rac1) and is expressed in breast tumor cells (e.g., SP-1 cell line). Immunoprecipitation and immunoblot analyses indicate that Tiam1 and the cytoskeletal protein, ankyrin, are physically associated as a complex in vivo. In particular, the ankyrin repeat domain (ARD) of ankyrin is responsible for Tiam1 binding. Biochemical studies and deletion mutation analyses indicate that the 11–amino acid sequence between amino acids 717 and 727 of Tiam1 (717GEGTDAVKRS727L) is the ankyrin-binding domain. Most importantly, ankyrin binding to Tiam1 activates GDP/GTP exchange on Rho GTPases (e.g., Rac1).Using an Escherichia coli–derived calmodulin-binding peptide (CBP)–tagged recombinant Tiam1 (amino acids 393–728) fragment that contains the ankyrin-binding domain, we have detected a specific binding interaction between the Tiam1 (amino acids 393–738) fragment and ankyrin in vitro. This Tiam1 fragment also acts as a potent competitive inhibitor for Tiam1 binding to ankyrin. Transfection of SP-1 cell with Tiam1 cDNAs stimulates all of the following: (1) Tiam1–ankyrin association in the membrane projection; (2) Rac1 activation; and (3) breast tumor cell invasion and migration. Cotransfection of SP1 cells with green fluorescent protein (GFP)–tagged Tiam1 fragment cDNA and Tiam1 cDNA effectively blocks Tiam1–ankyrin colocalization in the cell membrane, and inhibits GDP/GTP exchange on Rac1 by ankyrin-associated Tiam1 and tumor-specific phenotypes. These findings suggest that ankyrin–Tiam1 interaction plays a pivotal role in regulating Rac1 signaling and cytoskeleton function required for oncogenic signaling and metastatic breast tumor cell progression.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Ankyrin–Tiam1 Interaction Promotes Rac1 Signaling and Metastatic Breast Tumor Cell Invasion and Migration

Bourguignon

Zhu

Shao

et al. 2000

The Journal of Cell Biology

116

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“…The role of the small GTPase Rac-1 in epithelial cell proliferation and transformation has not been well characterized and may be cell type-dependent. It has been recently shown that Val-12 Rac can partially revert Ras-induced transformation of epithelial kidney cells, by promoting E-cadherin-mediated cell-cell adhesion (Hordijk et al 1997). On the other hand, in mammary epithelial cells Val-12 Rac has been shown to disrupt normal polarization and promote integrinmediated cell motility and invasiveness (Keely et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

1998

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Activating point mutations in the Ras oncogene occur in a large number of human tumors, especially of epithelial origin. In thyroid follicular cells, ectopic expression of oncogenic H-Ras results in growth factor-independent proliferation, loss of di erentiation and tumor formation in nude mice. In ®broblasts concomitant activation of the MAP kinase cascade and the small GTPase Rac-1 leads to full malignant transformation. We have tested the e ects of these key downstream mediators of Ras in thyroid epithelial cells, by stably expressing either a constitutively active form of MEK-1 (MEK DN3/S218E/S222D ), a constitutively active form of Rac-1 (Val12-Rac), or both. While the activation of one molecule or the other results in a weak phenotype, concomitant activation of both MEK-1 and Rac-1 in thyroid cells leads to growth factor-independent proliferation, morphological transformation and anchorage-independent growth. However, in contrast to Ras-transformed thyroid cells, the ones expressing the constitutively active forms of MEK-1 and Rac-1 maintain their di erentiate phenotype and fail to form tumors when injected into nude mice. Thus, in thyroid epithelial cells, concomitant activation of MEK-1 and Rac-1 can reproduce only a subset of the Rasinduced e ects and is not su cient to cause full malignant transformation. Signi®cantly, Ras-mediated increased proliferation and loss of di erentiation can be dissociated in these cells.

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“…Rac regulates formation of lamellipodia and membrane ru ing in various types of cultured cells (for reviews, see Hall, 1994Hall, , 1998. Rac regulates actin assembly at the adherens junction of the wing disc epithelium in Drosophila (Luo et al, 1994;Eaton et al, 1995), the formation of cadherin-dependent cell-cell adhesion in MDCK cells and human keratinocytes (Braga et al, 1997;Hordijk et al, 1997;Takaishi et al, 1997;, and tight junction in MDCK cells . Cdc42 regulates the formation of ®lopodia in various types of cells (for review, see Hall, 1998).…”

Section: Introductionmentioning

confidence: 99%

Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells

et al. 1999

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The Rho small G protein family consists of the Rho, Rac, and Cdc42 subfamilies and regulates various cell functions through reorganization of the actin cytoskeleton. We previously showed that the Rho subfamily regulates the formation of stress ®bers and focal adhesions whereas the Rac subfamily regulates the Ecadherin-based cell-cell adhesion in MDCK cells. We studied here the function of the Cdc42 subfamily, consisting of two members, Cdc42Hs and G25k, in cell adhesion, migration, and morphology of MDCK cells. For this purpose, we made and used MDCK cell lines stably expressing each of dominant active mutants of Cdc42Hs (sMDCK-Cdc42HsDA) and G25K (sMDCK-G25KDA). Actin ®laments at the cell-cell adhesion sites increased in both sMDCK-Cdc42HsDA and -G25KDA cells. Both E-cadherin and b-catenin, adherens junctional proteins, at the cell-cell adhesion sites also increased in both sMDCK-Cdc42HsDA and -G25KDA cells. Electron microscopic analysis revealed that sMDCKCdc42HsDA cells tightly contacted with each other throughout the lateral membranes. Moreover, both the HGF-and TPA-induced disruption of the cadherin-based cell-cell adhesion and the subsequent cell migration were inhibited in both sMDCK-Cdc42HsDA and -G25KDA cells. Co-expression of the dominant negative mutant of Rac1, a member of the Rac subfamily, with the dominant active mutant of Cdc42Hs did not inhibit the increased accumulation of actin ®laments at the cell-cell adhesion sites. These results suggest that the Cdc42 subfamily is involved in the cadherin-based cell-cell adhesion in a manner independent of the Rac subfamily. Furthermore, the cells were frequently enveloped by the large multinuclear cells in both sMDCK-Cdc42HsDA and -G25KDA cells. Video microscopic analysis revealed that the cells were engulfed by the large cells during cytokinesis.

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Inhibition of Invasion of Epithelial Cells by Tiam1-Rac Signaling

Cited by 415 publications

References 23 publications

Ankyrin–Tiam1 Interaction Promotes Rac1 Signaling and Metastatic Breast Tumor Cell Invasion and Migration

Ankyrin–Tiam1 Interaction Promotes Rac1 Signaling and Metastatic Breast Tumor Cell Invasion and Migration

Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells

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