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Gene Review

Tiam1  -  T cell lymphoma invasion and metastasis 1

Mus musculus

Synonyms: AI847750, D16Ium10, D16Ium10e, T-lymphoma invasion and metastasis-inducing protein 1, TIAM-1, ...
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Disease relevance of Tiam1

  • We show that the Rac-specific guanine nucleotide exchange factor Tiam1 (T-lymphoma invasion and metastasis 1) is required for the integrin-mediated laminin (LN)-5 deposition, spreading, and migration of keratinocytes [1].
  • Taken together, we believe that the linkage between CD44v3 isoform and the PHn-CC-EX domain of Tiam1 is required for HA stimulated Rac1 signaling and cytoskeleton-mediated tumor cell migration during breast cancer progression [2].
  • Here we show that overexpression of Tiam1 induces cell spreading and affects neurite outgrowth in N1E-115 neuroblastoma cells [3].
  • In line with this, knock-down of Tiam1 reduced the growth potential of human colorectal cancer cells and their ability to form E-cadherin-based adhesions, a prerequisite for local invasion of tumor cells [4].
  • Here we show that Tiam1, a selective Rac GTPase activator, is a Wnt-responsive gene expressed in the base of intestinal crypts and up-regulated in mouse intestinal tumors and human colon adenomas [4].

High impact information on Tiam1

  • Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins [5].
  • Cell clones that were invasive in vitro produced experimental metastases in nude mice, and transfection of truncated Tiam-1 cDNAs into noninvasive cells made these cells invasive [5].
  • In the selected invasive T lymphoma variants, proviral insertions were found within coding exons of the Tiam-1 gene, resulting in both truncated 5'-end and 3'-end transcripts that give rise to N- and C-terminal Tiam-1 protein fragments [5].
  • Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours [6].
  • Tiam1-deficient primary embryonic fibroblasts were also resistant to Ras(V12)-induced focus formation [6].

Chemical compound and disease context of Tiam1


Biological context of Tiam1

  • The Rac activator Tiam1 is required for (alpha)3(beta)1-mediated laminin-5 deposition, cell spreading, and cell migration [1].
  • Our data indicate that Tiam1-mediated activation of Rac in PAs controls TJ biogenesis and polarity in epithelial cells by association with and activation of the Par3-Par6-aPKC polarity complex [7].
  • Moreover, phosphorylation of Tiam1 in cells treated with pervanadate, a potent inhibitor of tyrosine phosphatases, was partially inhibited by the Src inhibitor SU6656 [8].
  • We have recently identified the invasion-inducing Tiam1 gene by proviral insertional mutagenesis [9].
  • The murine invasion-inducing Tiam1 gene maps to the distal end of chromosome 16, 3.8 cM centromeric of the Ets2 gene [10].

Anatomical context of Tiam1


Associations of Tiam1 with chemical compounds

  • The Tiam1/Rac1 structure highlights the interactions that catalyse nucleotide exchange on Rho family G proteins, and illustrates structural determinants dictating specificity between individual Rho family members and their associated Dbl-related guanine nucleotide exchange factors [14].
  • Unique for Tiam1 are an additional PH domain and a Discs-large homology region in the NH2-terminal part of the protein [11].
  • Overexpression of Tiam1 recruits the alpha 6 beta 1 integrin, a laminin receptor, to specific adhesive contacts at the cell periphery, which are different from focal contacts [3].
  • After subcellular fractionation, up to 50% of Tiam1 is recovered in the Triton X-100-insoluble high speed pellet that contains small protein complexes [15].
  • Lysophosphatidic acid induces threonine phosphorylation of Tiam1 in Swiss 3T3 fibroblasts via activation of protein kinase C [16].

Physical interactions of Tiam1

  • Coimmunoprecipitation studies of Rac2D57N with RhoGDI alpha and Tiam1 demonstrated increased binding of Rac2D57N to these upstream regulators of Rac signaling relative to the wild type [17].

Regulatory relationships of Tiam1


Other interactions of Tiam1

  • Oncogenic activity of Tiam1 and Rac1 in NIH3T3 cells [9].
  • Our studies indicate that Tiam1 is a key molecule in alpha3beta1-mediated activation of Rac, which is essential for proper production and secretion of LN5, a requirement for the spreading and migration of keratinocytes [1].
  • Similar to wild-type (WT) keratinocytes, Tiam1-deficient cells establish primordial E-cadherin-based adhesions, but subsequent junction maturation and membrane sealing are severely impaired [7].
  • Restoration of Rho activity in Tiam1-expressing cells by expression of V14Rho results in reversion of the epithelioid phenotype towards a migratory, fibroblastoid morphology [18].
  • The invasion-inducing T-lymphoma invasion and metastasis 1 (Tiam1) protein functions as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1 [3].
  • Immunoprecipitation experiments show that in migrating keratinocytes, Tiam1 associates with Par3 and PKCzeta [21].

Analytical, diagnostic and therapeutic context of Tiam1


  1. The Rac activator Tiam1 is required for (alpha)3(beta)1-mediated laminin-5 deposition, cell spreading, and cell migration. Hamelers, I.H., Olivo, C., Mertens, A.E., Pegtel, D.M., van der Kammen, R.A., Sonnenberg, A., Collard, J.G. J. Cell Biol. (2005) [Pubmed]
  2. CD44 interaction with tiam1 promotes Rac1 signaling and hyaluronic acid-mediated breast tumor cell migration. Bourguignon, L.Y., Zhu, H., Shao, L., Chen, Y.W. J. Biol. Chem. (2000) [Pubmed]
  3. The guanine nucleotide exchange factor Tiam1 affects neuronal morphology; opposing roles for the small GTPases Rac and Rho. Leeuwen, F.N., Kain, H.E., Kammen, R.A., Michiels, F., Kranenburg, O.W., Collard, J.G. J. Cell Biol. (1997) [Pubmed]
  4. The rac activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumor development. Malliri, A., Rygiel, T.P., van der Kammen, R.A., Song, J.Y., Engers, R., Hurlstone, A.F., Clevers, H., Collard, J.G. J. Biol. Chem. (2006) [Pubmed]
  5. Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Habets, G.G., Scholtes, E.H., Zuydgeest, D., van der Kammen, R.A., Stam, J.C., Berns, A., Collard, J.G. Cell (1994) [Pubmed]
  6. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Malliri, A., van der Kammen, R.A., Clark, K., van der Valk, M., Michiels, F., Collard, J.G. Nature (2002) [Pubmed]
  7. The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex. Mertens, A.E., Rygiel, T.P., Olivo, C., van der Kammen, R., Collard, J.G. J. Cell Biol. (2005) [Pubmed]
  8. Rac1 function is required for Src-induced transformation. Evidence of a role for Tiam1 and Vav2 in Rac activation by Src. Servitja, J.M., Marinissen, M.J., Sodhi, A., Bustelo, X.R., Gutkind, J.S. J. Biol. Chem. (2003) [Pubmed]
  9. Oncogenic activity of Tiam1 and Rac1 in NIH3T3 cells. van Leeuwen, F.N., van der Kammen, R.A., Habets, G.G., Collard, J.G. Oncogene (1995) [Pubmed]
  10. The invasion-inducing TIAM1 gene maps to human chromosome band 21q22 and mouse chromosome 16. Habets, G.G., van der Kammen, R.A., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., Hagemeijer, A., Collard, J.G. Cytogenet. Cell Genet. (1995) [Pubmed]
  11. Regulated membrane localization of Tiam1, mediated by the NH2-terminal pleckstrin homology domain, is required for Rac-dependent membrane ruffling and C-Jun NH2-terminal kinase activation. Michiels, F., Stam, J.C., Hordijk, P.L., van der Kammen, R.A., Ruuls-Van Stalle, L., Feltkamp, C.A., Collard, J.G. J. Cell Biol. (1997) [Pubmed]
  12. Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2. Tanaka, M., Ohashi, R., Nakamura, R., Shinmura, K., Kamo, T., Sakai, R., Sugimura, H. EMBO J. (2004) [Pubmed]
  13. Roles of STEF/Tiam1, guanine nucleotide exchange factors for Rac1, in regulation of growth cone morphology. Matsuo, N., Terao, M., Nabeshima, Y., Hoshino, M. Mol. Cell. Neurosci. (2003) [Pubmed]
  14. Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1. Worthylake, D.K., Rossman, K.L., Sondek, J. Nature (2000) [Pubmed]
  15. Targeting of Tiam1 to the plasma membrane requires the cooperative function of the N-terminal pleckstrin homology domain and an adjacent protein interaction domain. Stam, J.C., Sander, E.E., Michiels, F., van Leeuwen, F.N., Kain, H.E., van der Kammen, R.A., Collard, J.G. J. Biol. Chem. (1997) [Pubmed]
  16. Lysophosphatidic acid induces threonine phosphorylation of Tiam1 in Swiss 3T3 fibroblasts via activation of protein kinase C. Fleming, I.N., Elliott, C.M., Collard, J.G., Exton, J.H. J. Biol. Chem. (1997) [Pubmed]
  17. Rac2D57N, a dominant inhibitory Rac2 mutant that inhibits p38 kinase signaling and prevents surface ruffling in bone-marrow-derived macrophages. Abell, A.N., DeCathelineau, A.M., Weed, S.A., Ambruso, D.R., Riches, D.W., Johnson, G.L. J. Cell. Sci. (2004) [Pubmed]
  18. Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. Sander, E.E., ten Klooster, J.P., van Delft, S., van der Kammen, R.A., Collard, J.G. J. Cell Biol. (1999) [Pubmed]
  19. Characterization of STEF, a guanine nucleotide exchange factor for Rac1, required for neurite growth. Matsuo, N., Hoshino, M., Yoshizawa, M., Nabeshima, Y. J. Biol. Chem. (2002) [Pubmed]
  20. Phospholipase C-gamma, protein kinase C and Ca2+/calmodulin-dependent protein kinase II are involved in platelet-derived growth factor-induced phosphorylation of Tiam1. Fleming, I.N., Elliott, C.M., Exton, J.H. FEBS Lett. (1998) [Pubmed]
  21. The Par-Tiam1 complex controls persistent migration by stabilizing microtubule-dependent front-rear polarity. Pegtel, D.M., Ellenbroek, S.I., Mertens, A.E., van der Kammen, R.A., de Rooij, J., Collard, J.G. Curr. Biol. (2007) [Pubmed]
  22. Lentivirus-mediated silencing of Tiam1 gene influences multiple functions of a human colorectal cancer cell line. Liu, L., Zhang, Q., Zhang, Y., Wang, S., Ding, Y. Neoplasia (2006) [Pubmed]
  23. Loss of phosphatidylinositol 3-phosphate binding by the C-terminal Tiam-1 pleckstrin homology domain prevents in vivo Rac1 activation without affecting membrane targeting. Baumeister, M.A., Martinu, L., Rossman, K.L., Sondek, J., Lemmon, M.A., Chou, M.M. J. Biol. Chem. (2003) [Pubmed]
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