Tiam1, short for T lymphoma invasion and metastasis-inducing protein 1, is a Rac1 guanine nucleotide exchange factor (GEF). It promotes actin cytoskeletal remodeling, which is crucial for processes like dendritic and synaptic growth during hippocampal development [2]. It is also involved in multiple signaling pathways, such as the TIAM1-RAC1 axis, which is associated with various biological functions and diseases [1]. Genetic models, especially knockout (KO) or conditional knockout (CKO) mouse models, are valuable in studying Tiam1's functions.

In aortic aneurysm and dissection, S-nitrosylation of Septin2 at Cys111 enhanced the activation of the TIAM1-RAC1 axis in macrophages, promoting nuclear factor-κB signaling pathway-dependent inflammation and extracellular matrix degradation [1]. In neuropathic pain animal models, Tiam1 coordinated synaptic structural and functional plasticity in the spinal dorsal horn, and antisense oligonucleotides (ASO) targeting spinal Tiam1 alleviated neuropathic pain sensitivity [2]. In colon cancer, NSD2 methylated Tiam1 at K724, promoting Rac1 signaling activation and cancer metastasis, and an inhibitory peptide blocking the NSD2-Tiam1 interaction inhibited tumor metastasis [3]. In chronic pain, Tiam1-mediated synaptic plasticity in anterior cingulate cortex (ACC) neurons was involved in comorbid depression-like behaviors, and low-dose ketamine blocked this maladaptive plasticity to exert antidepressant-like effects [4]. In morphine tolerance and hyperalgesia, Tiam1-coordinated synaptic plasticity in the spinal nociceptive network was responsible for these side effects, and pharmacological blockade of Tiam1-Rac1 signaling prevented or reversed them [5]. In solid cancers, high Tiam1 expression was associated with poor overall survival (OS) and disease-free survival (DFS), as well as positive lymphatic metastasis [6,7]. In islet β-cells, Tiam1, along with Vav2, was a GEF for Rac1, playing both beneficial and harmful roles in islet function and dysfunction [8]. In neutrophils, Tiam1 controlled integrin-dependent responses, such as focal complexes, migration, degranulation, and NETs release, and was required for neutrophil recruitment and bacteria clearance in vivo, but it functioned differently from other Rac-GEFs [9]. In non-small-cell lung cancer (NSCLC), a TIAM1-TRIM28 complex in the nucleus promoted cell migration and invasion through epigenetic silencing of protocadherins [10].

In conclusion, Tiam1 is a key regulator in multiple biological processes, revealed through model-based research. Its functions in diseases such as aortic aneurysm, neuropathic pain, cancer, chronic pain-related depression, morphine-induced side effects, and immune cell responses highlight its importance as a potential therapeutic target. The use of KO/CKO mouse models has been instrumental in understanding Tiam1's roles in these disease areas.

References:

1. Zhang, Yan, Zhang, Hao, Zhao, Shuang, Xie, Liping, Ji, Yong. 2024. S-Nitrosylation of Septin2 Exacerbates Aortic Aneurysm and Dissection by Coupling the TIAM1-RAC1 Axis in Macrophages. In Circulation, 149, 1903-1920. doi:10.1161/CIRCULATIONAHA.123.066404. https://pubmed.ncbi.nlm.nih.gov/38357802/

2. Li, Lingyong, Ru, Qin, Lu, Yungang, Yao, Changqun, Tolias, Kimberley F. 2023. Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain. In Neuron, 111, 2038-2050.e6. doi:10.1016/j.neuron.2023.04.010. https://pubmed.ncbi.nlm.nih.gov/37146610/

3. Song, Da, Hu, Fuqing, Huang, Changsheng, Hu, Junbo, Wang, Guihua. 2023. Tiam1 methylation by NSD2 promotes Rac1 signaling activation and colon cancer metastasis. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2305684120. doi:10.1073/pnas.2305684120. https://pubmed.ncbi.nlm.nih.gov/38113258/

4. Ru, Qin, Lu, Yungang, Saifullah, Ali Bin, Tolias, Kimberley F, Li, Lingyong. 2022. TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain. In The Journal of clinical investigation, 132, . doi:10.1172/JCI158545. https://pubmed.ncbi.nlm.nih.gov/36519542/

5. Yao, Changqun, Fang, Xing, Ru, Qin, Tolias, Kimberley F, Li, Lingyong. . Tiam1-mediated maladaptive plasticity underlying morphine tolerance and hyperalgesia. In Brain : a journal of neurology, 147, 2507-2521. doi:10.1093/brain/awae106. https://pubmed.ncbi.nlm.nih.gov/38577773/

6. Ding, Jianlong, Yang, Fan, Wu, WeiFeng. . Tiam1 high expression is associated with poor prognosis in solid cancers: A meta-analysis. In Medicine, 98, e17529. doi:10.1097/MD.0000000000017529. https://pubmed.ncbi.nlm.nih.gov/31702612/

7. Yang, Caixia, Ma, Chenlin, Li, Yingchun, Mo, Peng, Yang, Yusheng. 2019. High Tiam1 expression predicts positive lymphatic metastasis and worse survival in patients with malignant solid tumors: a systematic review and meta-analysis. In OncoTargets and therapy, 12, 5925-5936. doi:10.2147/OTT.S191571. https://pubmed.ncbi.nlm.nih.gov/31413590/

8. Kowluru, Anjaneyulu. 2017. Tiam1/Vav2-Rac1 axis: A tug-of-war between islet function and dysfunction. In Biochemical pharmacology, 132, 9-17. doi:10.1016/j.bcp.2017.02.007. https://pubmed.ncbi.nlm.nih.gov/28202288/

9. Hornigold, Kirsti, Baker, Martin J, Machin, Polly A, Malliri, Angeliki, Welch, Heidi C E. 2023. The Rac-GEF Tiam1 controls integrin-dependent neutrophil responses. In Frontiers in immunology, 14, 1223653. doi:10.3389/fimmu.2023.1223653. https://pubmed.ncbi.nlm.nih.gov/38077328/

10. Ginn, Lucy, Maltas, Joe, Baker, Martin J, Hurlstone, Adam, Malliri, Angeliki. 2023. A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2300489120. doi:10.1073/pnas.2300489120. https://pubmed.ncbi.nlm.nih.gov/37748077/