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

• In this study, we show that the Rac-specific guanine nucleotide exchange factor Tiam1 (T-lymphoma invasion and metastasis) controls the cell polarity of epidermal keratinocytes [7].

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

• Here we show that both in fibroblasts and COS cells, membrane localization of Tiam1 is required for the induction of membrane ruffling [11].
• Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2 [12].
• Moreover, Tiam1 deficiency impairs keratinocyte migration in vitro and reepithelialization of excision wounds in mouse skin [1].
• The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex [7].
• We reveal that, in primary hippocampal neurons, STEF/Tiam1 are localized within growth cones and essential for formation of growth cone lamellipodia, eventually contributing to neurite growth [13].

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

• Tiam1-/- cells are unable to activate Rac upon alpha3beta1-mediated adhesion to an exogenous LN5 substrate [1].
• Activation of Rac by Tiam1 induces an epithelial-like morphology with functional cadherin-based adhesions and inhibits migration of fibroblasts [18].
• Suppression of endogenous STEF and Tiam1 activities in N1E-115 cells by ectopically expressed PHnTSS STEF resulted in inhibition of neurite outgrowth in serum-starved conditions, which usually induce neurite formation [19].
• Phospholipase C-gamma, protein kinase C and Ca2+/calmodulin-dependent protein kinase II are involved in platelet-derived growth factor-induced phosphorylation of Tiam1 [20].

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

• A detailed mutational analysis, in combination with confocal laser scanning microscopy and immunoelectron microscopy, demonstrates that the NH2-terminal PH domain of Tiam1, but not the DH-adjacent PH domain, is essential for membrane association [11].
• Using an orthotopic xenograft model in nude mice, we confirmed that Tiam1 silencing could reduce tumor growth by subcutaneous injection and could suppress lung and liver metastases of colorectal cancer cells [22].
• Immunofluorescence studies showed that membrane targeting of Tiam-1 was essentially unaffected by mutations in the C-terminal PH domain [23].
• Immunoprecipitation and immunoblot analyses indicate that both the CD44v3 isoform and the Tiam1 protein are expressed in SP1 cells and that these two proteins are physically associated as a complex in vivo [2].

References