Disease relevance of TIAM1

• Cloning and characterization of T-cell lymphoma invasion and metastasis 2 (TIAM2), a novel guanine nucleotide exchange factor related to TIAM1 [1].
• TIAM1 is a guanine nucleotide exchange factor that was identified in a screen for genes that increase the invasiveness of T lymphoma cell lines (Habets et al., 1994, Cell 77(4): 537-549) [1].
• Interestingly, Tiam1 transcripts were found in virtually all analysed tumor cell lines of human and rodent origin including B- and T-lymphomas, neuroblastomas, melanomas and carcinomas [2].
• The RacGEF Tiam1 inhibits migration and invasion of metastatic melanoma via a novel adhesive mechanism [3].
• The expression of Tiam1 gene was highly related to the metastatic potential of colorectal carcinoma cells [4].

High impact information on TIAM1

• Both Tiam1 and activated RacV12 promote invasiveness of T lymphoma cells [5].
• These data suggest an invasion-suppressor role for Tiam1 and Rac in epithelial cells [5].
• Ectopic expression of Tiam1 or RacV12 inhibited hepatocyte growth factor-induced scattering by increasing E-cadherin-mediated cell-cell adhesion accompanied by actin polymerization at cell-cell contacts [5].
• In epithelial Madin-Darby canine kidney (MDCK) cells, Tiam1 localized to adherens junctions [5].
• Tiam1 encodes an exchange factor for the Rho-like guanosine triphosphatase Rac [5].

Chemical compound and disease context of TIAM1

• Thirty subjects with hypertension on hydrochlorothiazide (HCTZ) were randomized to TIAM or CLON [6].

Biological context of TIAM1

• Overexpression of Tiam1 in metastatic melanoma cells converted the constitutive mesenchymal phenotype into an epithelial-like phenotype [3].
• Tiam1 (T lymphoma invasion and metastasis 1), a guanine nucleotide exchange factor that activates Rac, is an important regulator of cell shape and invasiveness in epithelial cells and fibroblasts [3].
• Tiam1 gene expression and its significance in colorectal carcinoma [4].
• As a specific guanine nucleotide exchange factor of Rac1, Tiam1 (T-lymphoma invasion and metastasis inducing protein 1) is involved in a number of cellular events, such as cytoskeleton reorganization, cell adhesion, and cell migration [7].
• Transwell assay showed that down-regulation of endogenous Tiam1 by anti-Tiam1 can reduce the in vitro invasiveness of 95D cells [7].

Anatomical context of TIAM1

• Sequence of the human invasion-inducing TIAM1 gene, its conservation in evolution and its expression in tumor cell lines of different tissue origin [2].
• We have identified a gene, T-cell lymphoma invasion and metastasis 2 (HGMW-approved symbol TIAM2), with significant identity to the carboxyl-terminal region of the TIAM1 and mapped it to 6q25 [1].
• Our results suggested that Tiam1 signaling contributed to the invasion and metastasis of the human giant-cell lung carcinoma cells [7].
• Moreover, in 1321N1 astrocytoma cells, translocation of Tiam1 to the cytosol, following receptor-mediated stimulation of PtdIns(4,5)P(2) breakdown, correlates with decreased Rac1-GTP levels, indicating that membrane-association is required for GDP/GTP exchange on Rac1 [8].
• Inositol phospholipids regulate the guanine-nucleotide-exchange factor Tiam1 by facilitating its binding to the plasma membrane and regulating GDP/GTP exchange on Rac1 [8].

Associations of TIAM1 with chemical compounds

• Tiam1 is a member of the Dbl family of guanine nucleotide exchange factors that activate Rho family GTPases [9].
• Certain phosphoinositides also stimulated Tiam1 activity but were less potent than ascorbyl stearate [9].
• Finally, the data demonstrate that PtdIns(4,5)P(2) and PtdIns(3,4,5)P(3) bind to the same pleckstrin homology domain in Tiam1 and that soluble inositol phosphates appear to compete with lipids for this binding [8].
• Finally, we demonstrate that in cells treated with ceramide, cleavage of TIAM1 coincided with the inactivation of endogenous Rac [10].
• While the PH domains of intersectin and Dbs promiscuously bind several multiphosphorylated phosphoinositides, Tiam1 selectively interacts with phosphatidylinositol 3-phosphate (K(D) approximately 5-10 microm) [11].

Physical interactions of TIAM1

• Tiam1 interacts with the NMDA receptor and is phosphorylated in a calcium-dependent manner in response to NMDA receptor stimulation [12].

Regulatory relationships of TIAM1

• These results suggest that nm23H1 negatively regulates Tiam1 and inhibits Rac1 activation in vivo [13].
• The reverse transition from mesenchymal invasive to a resident epithelial-like phenotype implicates a role for Tiam1/Rac signaling in the control of cell-cell contacts through a novel ALCAM-mediated mechanism [3].
• In contrast, Rac2 displays a slower nucleotide association and is more efficiently activated by the Rac-GEF Tiam1 [14].
• Stable overexpression of Tiam1 or constitutively active V12-Rac1 in a human renal cell carcinoma cell line (clearCa-28) strongly inhibited cell migration by promoting E-cadherin-mediated cell-cell adhesion [15].

Other interactions of TIAM1

• Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1 [13].
• Regulation of Tiam1 nucleotide exchange activity by pleckstrin domain binding ligands [9].
• Blocking E-cadherin-mediated adhesion by E-cadherin-specific HAV peptides allowed cells to migrate, but was not sufficient to antagonize Tiam1- and V12-Rac1-induced inhibition of Matrigel invasion, suggesting that Rac may influence invasion also through other mechanisms [15].
• In group A tumors, Rac was positive in 10/35 (28%), cdc42 was positive in 12/35 (34%) and Tiam1 was positive in 30/35 (85%) tumors [16].
• Here we demonstrate that the conserved PH domains of three distinct Dbl family proteins, intersectin, Dbs, and Tiam1, selectively bind lipid vesicles only when phosphoinositides are present [11].

Analytical, diagnostic and therapeutic context of TIAM1

• METHODS: Expressions of Tiam1 gene in 8 colorectal carcinoma cell lines were detected by reverse transcriptase-polymerase chain reaction [4].
• The partial nucleotide sequence of one of the differentially expressed clones obtained after treatment with bufalin was identical to that of the human gene for Tiam1 [17].
• Univariate analysis showed a statistically significant association of strong Tiam1 overexpression with decreased disease-free survival (DFS) (P=0.03) [18].
• In the present study, Tiam1 expression was analysed in benign secretory epithelium, pre-neoplastic high-grade prostatic intraepithelium neoplasia (HG-PIN) and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry [18].

References