| Note | The human Tiam1 gene encodes a protein of 1,591 amino acids with a predicted molecular mass of 177 kD and several distinct domains. |
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| | Domain structure of the Tiam1 protein. Myr, myristoylation site; P, PEST sequence; PHn, N-terminal Pleckstrin homology domain; CC, coiled-coil region; Ex, extended structure; RBD, Ras-binding domain; PDZ, PSD-95/DlgA/ZO-1 domain; DH, Dbl homology domain; PHc, C-terminal Pleckstrin homology domain. PI, phospho-inositides. |
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| Description | The Tiam1 protein is myristoylated at its N-terminus and contains 2 N-terminal PEST domains, an N-terminal pleckstrin homology domain (PHn), a coiled-coil region with adjacent sequence (CC-Ex), a Ras-binding domain (RBD), a PSD-95/DlgA/ZO-1 domain (PDZ) and a catalytic Dbl homology (DH)-PH (PHc) combination. While the PHn-CC-Ex domain of Tiam1 is crucial for membrane localisation of the protein, the DH-PHc combination is characteristic for all members of the Dbl-like family of guanine nucleotide exchange factors (GNEFs) (Engers, 2009). |
| Expression | Tiam1 is ubiquitously expressed with highest expression levels in brain and testis. Accordingly, many different cell lines have been shown to express Tiam1 on the RNA and/or protein level. |
| Localisation | Tiam1 is primarily located in the cytoplasm of cells, but upon activation it is translocated to the plasma membrane. The activity of Tiam1 is regulated by different mechanisms: relief of intramolecular inhibition, post-translational modifications (e.g. threonine phosphorylation) and interaction with other proteins, including Nm23-H1, c-Myc, CD44, Ankyrin, Spinophilin, JIP2/IB2, Par3, Arp2/3, Ras, Trk-B, Rac, phospho-inositides (Mertens et al., 2003; Minard et al., 2004; Engers, 2009). |
| Function | Tiam1 is a specific activator of the Rho-like GTPase Rac and is implicated in the regulation of different cell biological functions, including cell polarity, adhesion, migration, invasion, metastasis and carcinogenesis. Originally, Tiam1 has been identified as a gene that confers an invasive and metastatic phenotype to otherwise noninvasive murine T-lymphoma cells. In contrast, Tiam1 inhibits migration and invasion of epithelial cells by promoting E-cadherin-mediated cell-cell adhesion and by shifting the balance between distinct invasion-promoting matrix metalloproteinases (MMP-2 and -9) and invasion-inhibiting tissue inhibitors of metalloproteinases (TIMP-1 and -2) towards the TIMPs. However, in other studies Tiam1 was shown to promote migration and invasion of epithelial cells. These seemingly opposing effects of Tiam1 on migration and invasion in epithelial cells depend at least partly on the cell type studied, the fact as to whether or not the cell substrate used affects the formation of E-cadherin-mediated cell-cell adhesion, and the relative levels of Rac and Rho. Aside from these functions Tiam1 has also been implicated in the development of malignant tumors either as a mediator of oncogenic Ras-signaling (in skin tumors) or as a Wnt-responsive gene (in intestinal tumors) (Engers, 2009).
Morphologically, overexpression of Tiam1 in different cell types induces a distinct phenotype, characterised by large flat cells with epithelioid or sickle-shaped morphology and extensive membrane ruffling. In addition, many of these Tiam1-transfected cells are either polynucleated or contain large numbers of pinocytic vesicles (Minard et al., 2004). Mutational analysis revealed that the PHn-CC-Ex domain is required for membrane localisation of the protein and Tiam1-induced membrane ruffling. |
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| | Characteristic phenotype of Tiam1-transfected cells as determined by confocal laser scanning microscopy: In comparison to untransfected control cells (left) Tiam1-transfected cells (right) are large, epithelioid and exhibit pronounced membrane ruffling (green, Tiam1; red, F-actin; yellow, colocalisation of Tiam1 with the actin cytoskeleton). |
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| Homology | 95 % identical to the mouse homolog, Tiam1 is conserved among vertrebrates. Still life (SIF) is the Drosophila homologue of Tiam1. |
| Entity | Prostate Cancer |
| Disease | Tiam1 protein expression was investigated by immunohistochemistry in prostate carcinomas. Tiam1 was found to be significantly stronger expressed in preneoplastic high grade prostate intraepithelial neoplasia (HG-PIN) and prostate carcinomas when compared to corresponding benign secretory epithelial cells (Engers et al., 2006). |
| Prognosis | Strong overexpression of Tiam1 in prostate cancer is significantly correlated with disease recurrence, the presence of lymph vessel invasion and high Gleason scores. In univariate analysis strong overexpression (e.g. ≥ 3.5-fold) of Tiam1 in prostate cancer predicted significantly decreased disease-free survival as compared to prostate cancer with weak (e.g. <3.5-fold) Tiam1 overexpression. Most importantly, this prognostic effect of strong Tiam1 overexpression remained significant in multivariate analysis, in which all well established prognostic factors in prostate cancer (e.g. preoperative PSA levels, pT stage, Gleason score) were included. |
| Oncogenesis | Observations that significantly increased Tiam1 expression was not only found in prostate cancer, but also in almost all analysed preneoplastic HG-PIN lesions, suggest that increased Tiam1 expression occurs early in prostate carcinoma development. As a consequence increased Tiam 1 expression might induce transcription of oncogenes or inhibit transcription of tumour suppressor genes, thus contributing to oncogenic transformation. |
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| Entity | Colon Carcinoma |
| Disease | Malliri et al. (2006) identified that Tiam1 is a Wnt-responsive gene which is upregulated in human colon adenomas and implicated in intestinal tumorigenesis. By comparing APC mutant Min (multiple intestinal neoplasia) mice expressing or lacking Tiam1, they found that Tiam1 deficiency significantly reduces the formation and growth of polyps in vivo. In line with this, knock-down of Tiam1 in human colorectal cancer cells inhibited cell proliferation as well as the ability of these cells to form E-cadherin-based adhesions. In already established tumors, the role of Tiam1 still has to be clarified. On the one hand Tiam1 appears to have protective effects as adenocarcinomas arisen in Tiam1-deficient mice were found to be more aggressive than those arisen in Tiam1 wild-type mice (Malliri et al., 2006). On the other hand overexpression of Tiam1 in SW480 colon cancer cells induced a metastatic phenotype, hence more aggressive behaviour of these cells (Minard et al., 2005). |
| Oncogenesis | Malliri et al. (2006) report a cross-talk between Tiam1/Rac and the canonical Wnt-signaling pathway that affects intestinal tumor formation and progression. |
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| Entity | Renal cell carcinoma |
| Disease | In renal cell carcinoma (RCC) cell lines Tiam1 expression was shown to be inversely correlated with in vitro invasiveness (Engers et al., 2000). In line with this, overexpression of Tiam1 or overexpression of constitutively active V12-Rac1 significantly inhibited migration and invasion of human RCC cells. While the effects on migration were largely dependent on E-cadherin-mediated cell-cell adhesion, inhibition of invasion resulted mainly from selective upregulation of TIMP-1 and TIMP-2 (Engers et al., 2001). |
| Oncogenesis | In a cohort of different human RCC cell lines and primary RCCs up to 5 different point mutations of the Tiam1 gene were found (Engers et al., 2000). One of these mutations (A441G) was found in 11.5 % of primary human RCCs, but not in the corresponding normal kidney tissues. By overexpression of mutated A441G-Tiam1 in NIH 3T3 cells this mutation was shown to be sufficient for oncogenic transformation in vitro. These data suggest that distinct mutations of the Tiam1 gene might be implicated in the development of a subset of human RCCs. |
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| Entity | Skin tumors |
| Disease | Malliri et al. (2002) investigated the role of the Rac activator Tiam1 in Ras-induced skin tumours in mice. Similar to their reports about the implication of Tiam1 in colon cancer, they found a reduced tumour burden and growth in Tiam1-deficient mice. The reduced tumor growth rate in Tiam1-deficient mice may be a result of increased apoptosis and reduced cell proliferation during initiation. Studies in Tiam1 heterozygous mice suggested that the Tiam1 gene dose affects the efficiency of Ras-dependent tumor initiation. These findings indicate the implication of Tiam1 in Ras-induced skin tumour initiation. However, similar to colon cancer, after tumour initiation Tiam1 expression seems to protect from malignant progression. Thus, the small number of tumours that arose in Tiam1-deficient mice acquired a more aggressive phenotype than tumours arisen in wild-type mice.
In line with this, Uhlenbrock et al. (2004) reported inhibition of migration and invasion by Tiam1 in metastatic melanoma cells. Tiam1 overexpression resulted in gain of cell-cell junctions that counteracted cell motility and invasion. |
| Oncogenesis | A role for Tiam1 in Ras-induced skin tumour formation has been described by Malliri et al. (2002) (see above). |
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| Entity | Retinoblastoma |
| Disease | Adithi et al. (2006) reported significantly increased Tiam1 expression in invasive retinoblastoma. |
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| Entity | Breast Cancer |
| Disease | Heregulin-beta1 (HRG) promotes motility, scattering and invasiveness of breast cancer cells. Adam et al. (2001) identified Tiam1 as a target of HRG signalling and showed that Tiam1 overexpression mimicks several HRG-induced phenotypic changes in breast cancer cells. In line with these observations, the migratory capacities of several breast cancer cell lines were found to correlate with Tiam1 expression levels (Minard et al., 2004). Moreover, in a small number of breast cancer tissue samples Tiam1 expression was found to correlate with a high tumor grade (Adam et al., 2001). |
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| Entity | Pancreatic adenocarcinoma |
| Disease | In a recent study Cruz-Monserrate et al. (2008) provide evidence that integrin alpha6beta4 promotes the migratory and invasive phenotype of pancreatic carcinoma cells through the Tiam1/Rac pathway in part through upregulation of Tiam1. |
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| Entity | Increased vascular permeability |
| Disease | Reorganization of the cytoskeleton and adhesive complexes provides the basis for increased vascular permeability implicated in various diseases. A recent study of Birukova et al. (2007) demonstrated a role for Tiam1/Rac in HGF-induced endothelial cell barrier protection. |
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| Tiam1 mutations in human renal-cell carcinomas. |
| Engers R, Zwaka TP, Gohr L, Weber A, Gerharz CD, and Gabbert HE. |
| Int J Cancer 2000; 88: 369-376. |
| PMID 11054665 |
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| Tiam1 overexpression potentiates heregulin-induced lymphoid enhancer factor-1/beta -catenin nuclear signaling in breast cancer cells by modulating the intercellular stability. |
| Adam L, Vadlamudi RK, McCrea P, and Kumar R. |
| J Biol Chem 2001; 276: 28443-28450. |
| PMID 11328805 |
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| Rac affects invasion of human renal cell carcinomas by up-regulating tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 expression. |
| Engers R, Springer E, Michiels F, Collard JG, and Gabbert HE. |
| J Biol Chem 2001; 276: 41889-41897. |
| PMID 11551917 |
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| Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. |
| Malliri A, van der Kammen RA, Clark K, van der Valk M, Michiels F, Collard JG.. |
| Nature 2002; 417: 867-871. |
| PMID 12075356 |
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| Regulation of Tiam1-Rac signalling. |
| Mertens AE, Roovers RC, and Collard JG. |
| FEBS Lett 2003; 546: 11-16. (Minireview) |
| PMID 12829230 |
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| The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression. |
| Minard ME, Kim LS, Price JE, and Gallick GE. |
| Breast Cancer Res Treat 2004; 84: 21-32. (Review) |
| PMID 14999151 |
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| The RacGEF Tiam1 inhibits migration and invasion of metastatic melanoma via a novel adhesive mechanism. |
| Uhlenbrock K, Eberth A, Herbrand U, Daryab N, Stege P, Meier F, Friedl P, Collard JG, and Ahmadian MR |
| J Cell Sci 2004; 117: 4863-4871. |
| PMID 15340013 |
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| The guanine nucleotide exchange factor Tiam1 increases colon carcinoma growth at metastatic sites in an orthotopic nude mouse model. |
| Minard ME, Herynk MH, Collard JG, Gallick GE. |
| Oncogene 2005; 24: 2568-2573. |
| PMID 15735692 |
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| Expressions of Rac1, Tiam1 and Cdc42 in retinoblastoma. |
| Adithi M, Venkatesan N, Kandalam M, Biswas J, and Krishnakumar S. |
| Exp Eye Res 2006; 83: 1446-1452. |
| PMID 17027002 |
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| Prognostic relevance of TiamI protein expression in prostate carcinomas. |
| Engers R, Mueller M, Walter A, Collard JG, Willers R, and Gabbert HE. |
| Brit J Cancer 2006; 95: 1081-1086. |
| PMID 17003780 |
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| The rac activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumor development. |
| Malliri A, Rygiel TP, van der Kammen RA, Song JY, Engers R, Hurlstone AF, Clevers H, and Collard JG. |
| J Biol Chem 2006; 281: 543-548. |
| PMID 16249175 |
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| Tiam1 regulates cell adhesion, migration and apoptosis in colon tumor cells. |
| Minard ME, Ellis LM, and Gallick GE. |
| Clin Exp Metastasis 2006; 23: 301-313. (Review) |
| PMID 17086355 |
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| HGF attenuates thrombin-induced endothelial permeability by Tiam1-mediated activation of the Rac pathway and by Tiam1/Rac-dependent inhibition of the Rho pathway. |
| Birukova AA, Alekseeva E, Mikaelyan A, and Birukov KG. |
| FASEB J 2007; 21: 2776-2786. |
| PMID 17428964 |
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| Rho GTPases: functions and association with cancer. |
| Ellenbroek SI and Collard JG. |
| Clin Exp Metastasis 2007; 24: 657-672. (Review) |
| PMID 18000759 |
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| Integrin alpha 6 beta 4 promotes migration, invasion through Tiam1 upregulation, and subsequent Rac activation. |
| Cruz-Monserrate Z and O'Connor KL. |
| Neoplasia 2008; 10: 408-417. |
| PMID 18472958 |
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| Tiam1 |
| Engers R. |
| In Encyclopedia of Cancer, edited by Schwab M, 2009 |
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