Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

TIAM1 (T-cell lymphoma invasion and metastasis 1)

Identity

Other namesFLJ36302
TIAM-1
HGNC (Hugo) TIAM1
LocusID (NCBI) 7074
Location 21q22.11
Location_base_pair Starts at 32490736 and ends at 32931290 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order The human gene maps to chromosome 21q22.1; between markers D21S298 and D21S404.
Gene orientation: forward strand.
Note Rho-like GTPases belong to the Ras superfamily and have crucial roles in many cellular processes, such as regulation of the actin cytoskeleton, cell migration, cell cycle progression, gene transcription and cell adhesion. Rho-like GTPases cycle between a GDP-bound inactive form and a GTP-bound active form and activation is catalysed by guanine nucleotide exchange factors (GNEFs) (Minard et al., 2004). The GNEF Tiam1 has been identified as an invasion- and metastasis-inducing gene in a murine T-lymphoma cell line and specifically activates the Rho-like GTPase Rac. Tiam1/Rac signaling controls the establishment and maintenance of E-cadherin-based cell-cell adhesions and loss of Tiam1 leads to epithelial-mesenchymal transition (EMT). Consequently, Tiam1/Rac signaling affects cell migration, invasion and tumor metastasis, but to some extent these effects seem to be cell type- and tumor type-dependent (Ellenbroek et al., 2007). Moreover, Tiam1 and Rac have been implicated in oncogenic transformation of cells.

DNA/RNA

Note 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.
 
  Localisation of the Tiam1 gene on human chromosome 21 and exon structure.
Description The Tiam1 gene constist of 29 exons encoding for a 7200 bp transcript.
Transcription 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.

Protein

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

Mutations

Note Investigations on mutations in the Tiam1 gene have only been reported in human renal-cell carcinomas.
 
  Domain structure of the Tiam1 protein and localisation of observed mutations (courtesy Engers et al., 2000).
Germinal None reported.
Somatic 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 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.
  
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.
  
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.
  
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).
  
Entity Retinoblastoma
Disease Adithi et al. (2006) reported significantly increased Tiam1 expression in invasive retinoblastoma.
  
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).
  
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.
  
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.
  

External links

Nomenclature
HGNC (Hugo)TIAM1   11805
Cards
AtlasTIAM1ID42557ch21q22
Entrez_Gene (NCBI)TIAM1  7074  T-cell lymphoma invasion and metastasis 1
GeneCards (Weizmann)TIAM1
Ensembl (Hinxton)ENSG00000156299 [Gene_View]  chr21:32490736-32931290 [Contig_View]  TIAM1 [Vega]
AceView (NCBI)TIAM1
Genatlas (Paris)TIAM1
WikiGenes7074
SOURCE (Princeton)NM_003253
Genomic and cartography
GoldenPath (UCSC)TIAM1  -  21q22.11   chr21:32490736-32931290 -  21q22.1   [Description]    (hg19-Feb_2009)
EnsemblTIAM1 - 21q22.1 [CytoView]
Mapping of homologs : NCBITIAM1 [Mapview]
OMIM600687   
Gene and transcription
Genbank (Entrez)AB209101 AK093621 AK124647 BC117192 BC117196
RefSeq transcript (Entrez)NM_003253
RefSeq genomic (Entrez)AC_000153 NC_000021 NC_018932 NT_011512 NW_001838706 NW_004929426
Consensus coding sequences : CCDS (NCBI)TIAM1
Cluster EST : UnigeneHs.517228 [ NCBI ]
CGAP (NCI)Hs.517228
Alternative Splicing : Fast-db (Paris)GSHG0019643
Alternative Splicing GalleryENSG00000156299
Gene ExpressionTIAM1 [ NCBI-GEO ]     TIAM1 [ SEEK ]   TIAM1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13009 (Uniprot)
NextProtQ13009  [Medical]
With graphics : InterProQ13009
Splice isoforms : SwissVarQ13009 (Swissvar)
Domaine pattern : Prosite (Expaxy)DH_1 (PS00741)    DH_2 (PS50010)    PDZ (PS50106)    PH_DOMAIN (PS50003)    RBD (PS50898)   
Domains : Interpro (EBI)DH-domain    GDS_CDC24_CS    PDZ    PH_like_dom    Pleckstrin_homology    Raf-like_ras-bd   
Related proteins : CluSTrQ13009
Domain families : Pfam (Sanger)PDZ (PF00595)    PH (PF00169)    RBD (PF02196)    RhoGEF (PF00621)   
Domain families : Pfam (NCBI)pfam00595    pfam00169    pfam02196    pfam00621   
Domain families : Smart (EMBL)PDZ (SM00228)  PH (SM00233)  RBD (SM00455)  RhoGEF (SM00325)  
DMDM Disease mutations7074
Blocks (Seattle)Q13009
PDB (SRS)2D8I    3KZD    3KZE    4GVC    4GVD    4K2O    4K2P   
PDB (PDBSum)2D8I    3KZD    3KZE    4GVC    4GVD    4K2O    4K2P   
PDB (IMB)2D8I    3KZD    3KZE    4GVC    4GVD    4K2O    4K2P   
PDB (RSDB)2D8I    3KZD    3KZE    4GVC    4GVD    4K2O    4K2P   
Human Protein AtlasENSG00000156299
Peptide AtlasQ13009
HPRD02820
IPIIPI00011400   IPI00747471   IPI00794857   IPI00794833   IPI00917569   
Protein Interaction databases
DIP (DOE-UCLA)Q13009
IntAct (EBI)Q13009
FunCoupENSG00000156299
BioGRIDTIAM1
InParanoidQ13009
Interologous Interaction database Q13009
IntegromeDBTIAM1
STRING (EMBL)TIAM1
Ontologies - Pathways
Ontology : AmiGOreceptor signaling protein activity  Rho guanyl-nucleotide exchange factor activity  phospholipid binding  cytosol  plasma membrane  cell-cell junction  small GTPase mediated signal transduction  regulation of Rho protein signal transduction  positive regulation of apoptotic process  ephrin receptor binding  neurotrophin TRK receptor signaling pathway  ephrin receptor signaling pathway  positive regulation of axonogenesis  regulation of small GTPase mediated signal transduction  apoptotic signaling pathway  
Ontology : EGO-EBIreceptor signaling protein activity  Rho guanyl-nucleotide exchange factor activity  phospholipid binding  cytosol  plasma membrane  cell-cell junction  small GTPase mediated signal transduction  regulation of Rho protein signal transduction  positive regulation of apoptotic process  ephrin receptor binding  neurotrophin TRK receptor signaling pathway  ephrin receptor signaling pathway  positive regulation of axonogenesis  regulation of small GTPase mediated signal transduction  apoptotic signaling pathway  
Pathways : KEGGRas signaling pathway    Rap1 signaling pathway    Chemokine signaling pathway    Regulation of actin cytoskeleton    Proteoglycans in cancer   
REACTOMETIAM1
Protein Interaction DatabaseTIAM1
Wikipedia pathwaysTIAM1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)TIAM1
SNP (GeneSNP Utah)TIAM1
SNP : HGBaseTIAM1
Genetic variants : HAPMAPTIAM1
1000_GenomesTIAM1 
ICGC programENSG00000156299 
Somatic Mutations in Cancer : COSMICTIAM1 
CONAN: Copy Number AnalysisTIAM1 
Mutations and Diseases : HGMDTIAM1
OMIM600687   
GENETestsTIAM1
Disease Genetic AssociationTIAM1
Huge Navigator TIAM1 [HugePedia]  TIAM1 [HugeCancerGEM]
Genomic VariantsTIAM1  TIAM1 [DGVbeta]
Exome VariantTIAM1
dbVarTIAM1
ClinVarTIAM1
snp3D : Map Gene to Disease7074
General knowledge
Homologs : HomoloGeneTIAM1
Homology/Alignments : Family Browser (UCSC)TIAM1
Phylogenetic Trees/Animal Genes : TreeFamTIAM1
Chemical/Protein Interactions : CTD7074
Chemical/Pharm GKB GenePA36514
Clinical trialTIAM1
Cancer Resource (Charite)ENSG00000156299
Other databases
Probes
Litterature
PubMed93 Pubmed reference(s) in Entrez
CoreMineTIAM1
iHOPTIAM1

Bibliography

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
 
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
 
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
 
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
 
Regulation of Tiam1-Rac signalling.
Mertens AE, Roovers RC, and Collard JG.
FEBS Lett 2003; 546: 11-16. (Minireview)
PMID 12829230
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
Rho GTPases: functions and association with cancer.
Ellenbroek SI and Collard JG.
Clin Exp Metastasis 2007; 24: 657-672. (Review)
PMID 18000759
 
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
 
Tiam1
Engers R.
In Encyclopedia of Cancer, edited by Schwab M, 2009
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

Contributor(s)

Written08-2008Michèle J Hoffmann, Rainer Engers
Institute for Pathology, Heinrich-Heine University, Moorenstr. 5, 40225 Duesseldorf, Germany

Citation

This paper should be referenced as such :
Hoffmann MJ, Engers R . TIAM1 (T-cell lymphoma invasion and metastasis 1). Atlas Genet Cytogenet Oncol Haematol. August 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/TIAM1ID42557ch21q22.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44518/1/08-2008-TIAM1ID42557ch21q22.pdf   [ Bibliographic record ]

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Apr 16 11:24:36 CEST 2014

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.