Affinage

TIAM2

Rho guanine nucleotide exchange factor TIAM2 · UniProt Q8IVF5

Length
1701 aa
Mass
190.1 kDa
Annotated
2026-04-28
26 papers in source corpus 18 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIAM2 (also called STEF) is a Rac1-selective guanine nucleotide exchange factor that transduces diverse upstream signals into spatially restricted Rac1 activation to control cell morphology, migration, and mechanosensing. Its DH domain catalyzes GDP–GTP exchange specifically on Rac1, with the flanking PHc domain enhancing catalytic activity and the PHn-TSS region mediating membrane targeting and Rap1 binding; the PDZ domain confers ligand specificity distinct from its paralog TIAM1 (PMID:10364228, PMID:11707441, PMID:21192692, PMID:18047838). TIAM2 is activated by PKA phosphorylation at Thr-749 and inhibited by ROCK phosphorylation at Thr-1662, and is recruited into the PAR-3–aPKC–PAR-6–Cdc42 polarity complex to couple Cdc42 signaling to Rac1-dependent lamellipodia formation, axon specification, and cortical neuronal migration (PMID:21460187, PMID:17320046, PMID:15723051, PMID:12912917). Beyond growth cones, TIAM2 operates at focal adhesions to drive microtubule-targeted FA disassembly and cell migration, at the nuclear envelope where it maintains perinuclear Rac1 activity, actin cap integrity, and nuclear mechanosensing, and downstream of RTK–PI3K signaling in cancer cells to promote Rac1-dependent invasion and epithelial–mesenchymal transition (PMID:20224579, PMID:29844364, PMID:34731623, PMID:21469146).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    Identifying TIAM2 as a Rac1-specific GEF resolved the question of whether additional tissue-restricted exchange factors existed beyond TIAM1 for Rac-family GTPases.

    Evidence In vitro GDP dissociation assays showed exchange activity on Rac1 but not RhoA or Cdc42; domain analysis identified DH, PH, PDZ, and TSS domains; brain-enriched expression confirmed by in situ hybridization

    PMID:10364228 PMID:10512681

    Open questions at the time
    • No crystal structure of the DH-PH catalytic unit
    • Endogenous regulation unknown
    • Functional redundancy with TIAM1 not addressed
  2. 2001 High

    Systematic domain dissection established that the DH domain provides catalytic GEF activity while the PHn-TSS region directs membrane localization, explaining how TIAM2 achieves spatially restricted Rac1 activation for neurite outgrowth.

    Evidence Deletion mutagenesis in N1E-115 cells with morphology readout; dominant-negative PHnTSS fragment blocked both STEF- and TIAM1-dependent neurite extension

    PMID:11707441

    Open questions at the time
    • Mechanism of PHc-mediated catalytic enhancement unclear
    • No structural basis for PHnTSS membrane targeting
  3. 2003 High

    In vivo loss-of-function demonstrated that TIAM2/Rac1 signaling is required for cortical neuronal migration and identified JNK as a downstream effector controlling microtubule dynamics.

    Evidence In utero electroporation of dominant-negative constructs in mouse embryonic brain; JNK inhibitor treatment phenocopied migration defect

    PMID:12912917

    Open questions at the time
    • Relative contributions of TIAM2 vs. TIAM1 in vivo not resolved
    • Downstream nuclear targets of JNK in migrating neurons unknown
  4. 2005 High

    Discovery that PAR-3 directly binds and recruits TIAM2 into the PAR-3–aPKC–PAR-6–Cdc42 polarity complex provided a molecular mechanism for Cdc42-to-Rac1 signal relay during axon specification and lamellipodia formation.

    Evidence Reciprocal co-immunoprecipitation and dominant-negative binding disruption in COS7 cells and hippocampal neurons; colocalization at axon tips

    PMID:15723051

    Open questions at the time
    • Structural basis of PAR-3–STEF interaction not determined
    • Whether PAR-3 modulates catalytic activity or only localization is unclear
  5. 2007 High

    Identification of opposing phosphoregulation—activating PKA at Thr-749 and inhibitory ROCK at Thr-1662—established TIAM2 as an integration node for antagonistic Rho and cAMP signaling pathways.

    Evidence In vitro kinase assays, phosphomimetic/phosphonull mutagenesis, FRET-based Rac1 biosensors, and neurite outgrowth assays in PC12D cells; Rap1–TSS interaction shown by co-IP with functional consequence on sAPPα secretion

    PMID:17320046 PMID:18047838 PMID:21460187

    Open questions at the time
    • In vivo phosphorylation stoichiometry unknown
    • Whether other kinases target the same sites not tested
    • Structural impact of Thr-1662 phosphorylation on DH domain not resolved
  6. 2010 High

    Demonstrating that TIAM2 is the GEF required for microtubule-dependent focal adhesion disassembly linked cytoskeletal crosstalk to Rac1-regulated cell migration beyond neurons.

    Evidence siRNA knockdown combined with nocodazole washout, live-cell FA dynamics imaging, and Rac1 activation assays

    PMID:20224579

    Open questions at the time
    • Identity of microtubule-associated adaptor delivering TIAM2 to FAs not determined
    • Contribution of TIAM2 vs. other GEFs to FA turnover in different cell types unclear
  7. 2011 High

    Quantitative comparison of TIAM1 and TIAM2 PDZ domains revealed distinct ligand specificities governed by four non-conserved residues, establishing a basis for non-redundant scaffold interactions.

    Evidence Combinatorial peptide library screening, quadruple mutagenesis converting TIAM1 PDZ specificity to TIAM2-like, double mutant cycle analysis

    PMID:21192692

    Open questions at the time
    • Physiological PDZ ligands of TIAM2 not identified in cells
    • Role of PDZ domain in any TIAM2-dependent biological process not tested
  8. 2011 Medium

    Gain-of-function studies in hepatocellular carcinoma cells showed that the short TIAM2 isoform (TIAM2S) drives epithelial–mesenchymal transition and invasive behavior, broadening TIAM2 function to cancer biology.

    Evidence Stable overexpression in HepG2, invasion assays, EMT marker Western blot, xenograft mouse model

    PMID:21469146

    Open questions at the time
    • Loss-of-function not performed in HCC
    • Mechanism connecting Rac1 activity to EMT transcriptional program undefined
    • Single cell line
  9. 2018 High

    Localization of TIAM2 at the nuclear envelope and demonstration that it controls perinuclear Rac1, actin cap integrity, nuclear morphology, and TAZ-dependent mechanotransduction revealed a previously unrecognized nuclear-proximal function.

    Evidence siRNA KD, FRET Rac1 biosensor, colocalization with Nesprin-2G and NMMIIB, traction force microscopy, nuclear stiffness assay, rescue by NE-targeted active Rac1

    PMID:29844364

    Open questions at the time
    • Direct binding partner anchoring TIAM2 at the nuclear envelope not identified
    • Whether this role is specific to TIAM2 or shared with TIAM1 not tested
  10. 2019 Medium

    Opposing effects of full-length and short TIAM2 isoforms on mouse t-haplotype transmission ratio distortion linked isoform-specific Rac1-GEF activity to sperm motility regulation.

    Evidence Transgenic mouse overexpression of each isoform with transmission ratio analysis

    PMID:30817801

    Open questions at the time
    • Biochemical mechanism by which the short isoform enhances distortion while the long isoform suppresses it is unclear
    • Rac1 activity not directly measured in sperm
  11. 2021 High

    Epistasis analysis placed TIAM2 downstream of the AXL–Gab1–PI3K axis as a non-redundant Rac-GEF controlling RTK-driven cancer cell migration, resolving how receptor tyrosine kinase signaling selects specific GEFs.

    Evidence siRNA KD of multiple GEFs, FRET Rac1 biosensor, live-cell imaging of ruffle dynamics, kinase inhibitor epistasis in lung cancer cells

    PMID:34731623

    Open questions at the time
    • Direct activation mechanism from PI3K to TIAM2 not resolved
    • Whether PH domain PIP3 binding drives this recruitment not tested
  12. 2023 Medium

    Discovery that NSUN2-mediated m5C modification stabilizes TIAM2 mRNA via YBX1 provided the first epitranscriptomic regulation mechanism, while CaMKIγ lipid raft coupling identified a new upstream activator pathway for STEF-Rac1 in neuritogenesis.

    Evidence m5C-seq with mRNA decay assays and YBX1 dependency in pancreatic cancer; lipidation mutants with raft fractionation and Rac1 activation in PC12 cells

    PMID:37393317 PMID:37601281

    Open questions at the time
    • YBX1-dependent mRNA stabilization not independently replicated
    • CaMKIγ–STEF physical interaction not demonstrated
    • In vivo relevance of m5C regulation of TIAM2 not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of TIAM2 autoinhibition and activation, the identity of PDZ domain ligands in vivo, the mechanism by which TIAM2 is anchored at the nuclear envelope, and whether TIAM2 and TIAM1 have truly non-redundant roles in neuronal migration in genetic knockouts.
  • No full-length or DH-PH crystal/cryo-EM structure
  • No conditional genetic knockout phenotype reported
  • Autoinhibitory mechanism not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005886 plasma membrane 5 GO:0005635 nuclear envelope 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 3 R-HSA-1500931 Cell-Cell communication 2
Partners
MAP1BMYH10NESPRIN2PARD3RAC1RAP1A
Complex memberships
PAR-3–aPKC–PAR-6–Cdc42 polarity complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 STEF/TIAM2 was identified as a novel guanine nucleotide exchange factor (GEF) that specifically activates Rac1 but not RhoA or Cdc42, as demonstrated by in vitro GDP dissociation assays. The protein contains two pleckstrin homology (PH) domains, a PDZ domain, and a Dbl homology (DH) domain. Expression of truncated STEF induced membrane ruffling with altered actin localization in cultured cells, confirming in vivo Rac1 activation. In vitro GDP dissociation assay, domain analysis, cell overexpression The Journal of biological chemistry High 10364228 10512681
1999 TIAM2 was independently cloned and demonstrated to have GDP-GTP exchange activity. Its transcript is expressed in brain (cerebrum, cerebellum) and testis, and in situ hybridization showed expression in the E13.5 telencephalon and adult cerebral cortex, hippocampus, and ependyma. Biochemical GEF assay, in situ hybridization Genomics High 10512681
2001 Domain dissection of STEF/TIAM2 revealed distinct functional roles: the PHnTSS domain mediates membrane association, the DH domain is responsible for catalytic (GEF) activity, and the PHc domain promotes catalytic activity. STEF-induced neurite-like processes in N1E-115 cells were Rac1-dependent, and a dominant-negative PHnTSS fragment inhibited both STEF and Tiam1, suppressing neurite outgrowth. Deletion mutagenesis, dominant-negative overexpression, cell morphology assay The Journal of biological chemistry High 11707441
2003 In vivo repression of STEF/Tiam1 (Rac1 activators) in the developing murine brain via in utero electroporation inhibited radial migration of cortical neurons without affecting differentiation, establishing STEF/TIAM2-Rac1 as required for neuronal migration. JNK was identified as a downstream effector of Rac1, regulating microtubule dynamics (MAP1B phosphorylation) in migrating neurons. In utero electroporation (dominant-negative/constitutively active constructs), JNK inhibitor treatment, immunostaining The EMBO journal High 12912917
2003 STEF/TIAM2 and Tiam1 localize within growth cones of primary hippocampal neurons and are essential for lamellipodial formation and neurite growth. STEF/Tiam1 mediate extracellular laminin signals and Cdc42 signals to activate Rac1 in growth cones. RhoA was shown to inhibit the STEF/Tiam1-Rac1 pathway. Dominant-negative expression, immunolocalization, growth cone morphology assay Molecular and cellular neurosciences Medium 14550769
2005 PAR-3 directly interacts with STEF/Tiam1 and recruits them into a PAR-3-aPKC-PAR-6-Cdc42-GTP complex. This complex mediates Cdc42-induced Rac activation and lamellipodia formation. Disruption of PAR-3-STEF binding inhibited Cdc42-induced lamellipodia but not filopodia. STEF accumulated at the tip of the growing axon in hippocampal neurons, colocalizing with PAR-3, contributing to neuronal polarity. Co-immunoprecipitation, dominant-negative binding disruption, cell morphology assay, immunofluorescence colocalization Nature cell biology High 15723051
2007 Rap1 physically and specifically associates with STEF/TIAM2 through its TSS region. Upon Epac activation, Rap1 recruits STEF via the TSS domain, which activates Rac1, mediating non-amyloidogenic APP processing (sAPPα secretion). A deleted TSS domain of STEF failed to activate Rac1 and dramatically decreased sAPPα secretion. Co-immunoprecipitation, deletion mutagenesis, sAPPα secretion assay FEBS letters Medium 18047838
2007 Rho-kinase (ROCK) phosphorylates STEF/TIAM2 at Thr1662 in vitro, inhibiting its function. Rho-kinase counteracted STEF-induced Rac1 activation in COS7 cells. Phosphorylation of STEF by Rho-kinase diminished its interaction with microtubule-associated protein 1B (MAP1B). A phosphomimetic STEF mutant showed weakened ability to enhance NGF-induced neurite outgrowth in PC12D cells. In vitro kinase assay, phosphomimetic mutagenesis, Co-IP, neurite outgrowth assay, Rho-kinase inhibitor (Y-27632) Biochemical and biophysical research communications High 17320046
2010 STEF/TIAM2 is the Rac GEF responsible for Rac activation during microtubule (MT) regrowth following nocodazole washout. STEF is required for MT-mediated focal adhesion (FA) targeting and disassembly; STEF-knockdown cells have enlarged FAs with reduced disassembly rates, leading to decreased cell migration speed. siRNA knockdown, nocodazole washout assay, live-cell imaging of FA dynamics, Rac activation assay EMBO reports High 20224579
2011 The PDZ domains of TIAM1 and TIAM2 have overlapping but distinct ligand specificities, as determined by combinatorial peptide library screening. Four non-conserved residues in the S(0) and S(-2) pockets of the TIAM1 PDZ domain are key determinants of ligand affinity and specificity; a TIAM1 PDZ quadruple mutant acquired TIAM2 PDZ specificity. Double mutant cycle analysis revealed energetic couplings in each pocket. Combinatorial peptide library, site-directed mutagenesis, peptide binding assays, double mutant cycle analysis Biochemistry High 21192692
2011 PKA phosphorylates STEF/TIAM2 at three residues (Thr-749, Ser-782, Ser-1562); Thr-749 phosphorylation is specifically critical for cAMP (dbcAMP)-induced Rac1 activation and neurite outgrowth in PC12D cells. STEF depletion drastically reduced dbcAMP-induced neurite outgrowth. FRET biosensors revealed that PKA activity became localized to neurite tips, contributing to local Rac1 activation at the same sites. FRET biosensors (Rac1, Cdc42, PIP3, PKA activity), siRNA knockdown, phosphomimetic/phosphonull mutagenesis, neurite outgrowth assay Molecular biology of the cell High 21460187
2011 TIAM2S (short form) expression in HepG2 cells promoted growth and invasiveness, upregulated N-cadherin and vimentin, and redistributed E-cadherin, indicating EMT induction. In vivo xenograft experiments showed TIAM2S converted non-invasive HCC cells into highly aggressive vascular tumors. Stable overexpression, invasion assays, Western blot for EMT markers, xenograft mouse model International journal of cancer Medium 21469146
2013 TIAM2 knockdown in NSCLC cells inhibited invasion, motility, and Rac1 activation (measured by GST-pulldown), and upregulated E-cadherin while downregulating MMP-3, Twist, and Snail, placing TIAM2 upstream of Rac1 and EMT gene regulation in lung cancer cells. siRNA knockdown, GST-pulldown (Rac1 activation assay), invasion/motility assays, Western blot Asian Pacific journal of cancer prevention Medium 24377522
2018 STEF/TIAM2 localizes at the nuclear envelope, co-localizing with Nesprin-2G and Non-muscle myosin IIB (NMMIIB), where it regulates perinuclear Rac1 activity. STEF depletion reduces apical perinuclear actin cables, increases nuclear height, impairs nuclear re-orientation, decreases perinuclear pMLC and myosin-generated tension, and reduces nuclear stiffness and TAZ-regulated gene expression. Targeting active Rac1 to the nuclear envelope rescued the actin cap phenotype. siRNA knockdown, FRET-based Rac1 biosensor, immunofluorescence colocalization, traction force microscopy, nuclear stiffness assay, rescue by NE-targeted active Rac1 Nature communications High 29844364
2019 TIAM2 is expressed in two isoforms (full-length Tiam2l and short Tiam2s) in mouse sperm, acting oppositely on t-haplotype transmission ratio distortion. Tiam2s (expressed at higher levels from the t-allele) enhances t-haplotype sperm transmission while Tiam2l suppresses it. Transgenic approaches confirmed these opposite effects, linking TIAM2 isoform-specific Rac1-GEF activity to sperm motility regulation. Transgenic mouse overexpression, transmission ratio analysis, isoform-specific expression analysis PLoS genetics Medium 30817801
2021 FARP1, ARHGEF39, and TIAM2 are identified as essential Rac-GEFs downstream of EGFR and c-Met receptor tyrosine kinases for Rac1-mediated lung cancer cell migration. These GEFs operate non-redundantly, each controlling distinctive aspects of ruffle dynamics. The AXL-Gab1-PI3K axis was identified as the key upstream signaling pathway conferring pro-motility traits downstream of EGFR and acting through TIAM2. siRNA knockdown, Rac1 FRET biosensor, live-cell imaging of ruffle dynamics, epistasis analysis with kinase inhibitors Cell reports High 34731623
2023 NSUN2-mediated m5C modification of TIAM2 mRNA stabilizes it in a YBX1-dependent manner. Loss of NSUN2 reduced m5C modification and accelerated TIAM2 mRNA decay, reducing TIAM2 protein levels. NSUN2 also enhanced TIAM2 transcription. The NSUN2/TIAM2 axis promotes EMT in pancreatic cancer cells. m5C-seq, RNA-seq, lentiviral knockdown/overexpression, mRNA decay assay, YBX1 co-regulation analysis Cell death discovery Medium 37393317
2023 Dually lipidated CaMKIγ (prenylated and palmitoylated) functionally couples to a compartmentalized STEF-Rac1 pathway at lipid rafts to promote neurite extension in PC12 cells. Palmitoylation is specifically required for lipid raft association and for activating STEF-Rac1-dependent neuritogenesis; prenylation alone is insufficient. Lipidation mutants, cholesterol-enriched raft fractionation, Rac1 activation assay, neuritogenesis rescue assay in CaMKIγ-deficient PC12 cells Frontiers in cellular neuroscience Medium 37601281

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nature cell biology 313 15723051
2003 The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration. The EMBO journal 258 12912917
1999 Identification of the stef gene that encodes a novel guanine nucleotide exchange factor specific for Rac1. The Journal of biological chemistry 96 10364228
2010 The Rac activator STEF (Tiam2) regulates cell migration by microtubule-mediated focal adhesion disassembly. EMBO reports 77 20224579
2001 Characterization of STEF, a guanine nucleotide exchange factor for Rac1, required for neurite growth. The Journal of biological chemistry 76 11707441
2018 STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap. Nature communications 47 29844364
2003 Roles of STEF/Tiam1, guanine nucleotide exchange factors for Rac1, in regulation of growth cone morphology. Molecular and cellular neurosciences 46 14550769
2023 NSUN2 stimulates tumor progression via enhancing TIAM2 mRNA stability in pancreatic cancer. Cell death discovery 44 37393317
2011 Expression of T-cell lymphoma invasion and metastasis 2 (TIAM2) promotes proliferation and invasion of liver cancer. International journal of cancer 44 21469146
1999 Cloning and characterization of T-cell lymphoma invasion and metastasis 2 (TIAM2), a novel guanine nucleotide exchange factor related to TIAM1. Genomics 41 10512681
2007 Epac signaling pathway involves STEF, a guanine nucleotide exchange factor for Rac, to regulate APP processing. FEBS letters 33 18047838
2011 Distinct ligand specificity of the Tiam1 and Tiam2 PDZ domains. Biochemistry 32 21192692
2021 FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma. Cell reports 29 34731623
2011 Phosphorylation of STEF/Tiam2 by protein kinase A is critical for Rac1 activation and neurite outgrowth in dibutyryl cAMP-treated PC12D cells. Molecular biology of the cell 28 21460187
2022 TIAM2 Contributes to Osimertinib Resistance, Cell Motility, and Tumor-Associated Macrophage M2-like Polarization in Lung Adenocarcinoma. International journal of molecular sciences 27 36142328
2019 Two isoforms of the RAC-specific guanine nucleotide exchange factor TIAM2 act oppositely on transmission ratio distortion by the mouse t-haplotype. PLoS genetics 25 30817801
2007 Rho-kinase modulates the function of STEF, a Rac GEF, through its phosphorylation. Biochemical and biophysical research communications 24 17320046
2002 Expression of stef, an activator of Rac1, correlates with the stages of neuronal morphological development in the mouse brain. Mechanisms of development 22 11900975
2013 TIAM2 enhances non-small cell lung cancer cell invasion and motility. Asian Pacific journal of cancer prevention : APJCP 20 24377522
2019 The Fibroblast TIAM2 Promotes Lung Cancer Cell Invasion and Metastasis. Journal of Cancer 15 31205545
2021 The invasive alien red-eared slider turtle, Trachemys scripta, as a carrier of STEF-disease pathogens. Fungal biology 10 35078582
2023 Lipidation states orchestrate CLICK-III/CaMKIγ's stepwise association with Golgi and rafts-enriched membranes and specify its functional coupling to STEF-Rac1-dependent neurite extension. Frontiers in cellular neuroscience 4 37601281
2024 Verbascum ponticum (Stef.) Extract Induces Lung Cancer Apoptosis via Mitochondrial-Dependent Apoptosis Pathway. Life (Basel, Switzerland) 3 39598318
2022 TIAM2 promotes proliferation and invasion of osteosarcoma cells by activating the JAK2/STAT3 signaling pathway. Journal of bone oncology 3 36419799
2026 TIAM2 and ADCY7 polymorphisms and their association with feed efficiency in Huaibei partridge chickens. Poultry science 0 42035529
2024 The analysis on Tiam2 for expression in esophageal carcinoma: A descriptive study. Medicine 0 39093764