TIAM1 (T-cell lymphoma invasion and metastasis 1)

2008-08-01   Michèle J Hoffmann , Rainer Engers 

Institute for Pathology, Heinrich-Heine University, Moorenstr. 5, 40225 Duesseldorf, Germany





The ensemble database shows five Tiam1 transcripts, only one of which is encoding for the full length protein. Two transcripts are not translated and two others encode only for parts of the Tiam1 protein.
Atlas Image
Localisation of the Tiam1 gene on human chromosome 21 and exon structure.


The Tiam1 gene constist of 29 exons encoding for a 7200 bp transcript.


Tiam1 is expressed in almost all adult tissues with highest expression levels in brain and testis. Tiam1 is also expressed during embryogenesis as Tiam1 mRNA is detectable from day 10 onwards in mice.



The human Tiam1 gene encodes a protein of 1,591 amino acids with a predicted molecular mass of 177 kD and several distinct domains.
Atlas Image
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.


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).


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.


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).


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.
Atlas Image
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).


95 % identical to the mouse homolog, Tiam1 is conserved among vertrebrates. Still life (SIF) is the Drosophila homologue of Tiam1.



Investigations on mutations in the Tiam1 gene have only been reported in human renal-cell carcinomas.
Atlas Image
Domain structure of the Tiam1 protein and localisation of observed mutations (courtesy Engers et al., 2000).


None reported.


A study on human renal cell carcinomas (RCCs) reported up to five different point mutations in RCC cell lines (Engers et al., 2000). One of these mutations (A441G) was located in the N-terminal PH domain, which is essential for membrane localisation and functional activity of Tiam1. This mutation was found in 11.5 % of primary human RCCs, but not in the corresponding normal kidney tissues. Stable overexpression of A441G-Tiam1 proved to be sufficient for oncogenic transformation of NIH 3T3 cells in vitro.

Implicated in

Entity name
Prostate Cancer
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).
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.
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.
Entity name
Colon Carcinoma
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).
Malliri et al. (2006) report a cross-talk between Tiam1/Rac and the canonical Wnt-signaling pathway that affects intestinal tumor formation and progression.
Entity name
Renal cell carcinoma
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).
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.
Entity name
Skin tumors
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.
A role for Tiam1 in Ras-induced skin tumour formation has been described by Malliri et al. (2002) (see above).
Entity name
Adithi et al. (2006) reported significantly increased Tiam1 expression in invasive retinoblastoma.
Entity name
Breast Cancer
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).
Entity name
Pancreatic adenocarcinoma
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.
Entity name
Increased vascular permeability
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.


Pubmed IDLast YearTitleAuthors
113288052001Tiam1 overexpression potentiates heregulin-induced lymphoid enhancer factor-1/beta -catenin nuclear signaling in breast cancer cells by modulating the intercellular stability.Adam L et al
170270022006Expressions of Rac1, Tiam1 and Cdc42 in retinoblastoma.Adithi M et al
174289642007HGF 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 et al
184729582008Integrin alpha 6 beta 4 promotes migration, invasion through Tiam1 upregulation, and subsequent Rac activation.Cruz-Monserrate Z et al
180007592007Rho GTPases: functions and association with cancer.Ellenbroek SI et al
170037802006Prognostic relevance of Tiam1 protein expression in prostate carcinomas.Engers R et al
115519172001Rac affects invasion of human renal cell carcinomas by up-regulating tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 expression.Engers R et al
110546652000Tiam1 mutations in human renal-cell carcinomas.Engers R et al
162491752006The rac activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumor development.Malliri A et al
120753562002Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours.Malliri A et al
128292302003Regulation of Tiam1-Rac signalling.Mertens AE et al
170863552006Tiam1 regulates cell adhesion, migration and apoptosis in colon tumor cells.Minard ME et al
157356922005The guanine nucleotide exchange factor Tiam1 increases colon carcinoma growth at metastatic sites in an orthotopic nude mouse model.Minard ME et al
149991512004The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression.Minard ME et al
153400132004The RacGEF Tiam1 inhibits migration and invasion of metastatic melanoma via a novel adhesive mechanism.Uhlenbrock K et al

Other Information

Locus ID:

NCBI: 7074
MIM: 600687
HGNC: 11805
Ensembl: ENSG00000156299


dbSNP: 7074
ClinVar: 7074
TCGA: ENSG00000156299


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Tight junctionKEGGko04530
Regulation of actin cytoskeletonKEGGko04810
Tight junctionKEGGhsa04530
Regulation of actin cytoskeletonKEGGhsa04810
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
p75 NTR receptor-mediated signallingREACTOMER-HSA-193704
Cell death signalling via NRAGE, NRIF and NADEREACTOMER-HSA-204998
NRAGE signals death through JNKREACTOMER-HSA-193648
Signaling by Rho GTPasesREACTOMER-HSA-194315
Rho GTPase cycleREACTOMER-HSA-194840
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (12/13) signalling eventsREACTOMER-HSA-416482
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
EPH-Ephrin signalingREACTOMER-HSA-2682334
EPHB-mediated forward signalingREACTOMER-HSA-3928662
EPH-ephrin mediated repulsion of cellsREACTOMER-HSA-3928665

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
161953732005Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and alpha-actinin.115
208267922010miR-21 and miR-31 converge on TIAM1 to regulate migration and invasion of colon carcinoma cells.109
154797392004Rap1 promotes cell spreading by localizing Rac guanine nucleotide exchange factors.108
128107172003Rac1 function is required for Src-induced transformation. Evidence of a role for Tiam1 and Vav2 in Rac activation by Src.64
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
177027462007CD44 regulates hepatocyte growth factor-mediated vascular integrity. Role of c-Met, Tiam1/Rac1, dynamin 2, and cortactin.61
256548112015By downregulating TIAM1 expression, microRNA-329 suppresses gastric cancer invasion and growth.58
231422822013MiR-29c suppresses invasion and metastasis by targeting TIAM1 in nasopharyngeal carcinoma.51
240464472013eNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and Rho GTPases.46
204447032010miR-10b targets Tiam1: implications for Rac activation and carcinoma migration.44


Michèle J Hoffmann ; Rainer Engers

TIAM1 (T-cell lymphoma invasion and metastasis 1)

Atlas Genet Cytogenet Oncol Haematol. 2008-08-01

Online version: http://atlasgeneticsoncology.org/gene/42557/tiam1-(t-cell-lymphoma-invasion-and-metastasis-1)