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The RAC activator TIAM1 antagonises malignant progression by regulating cell‒cell adhesion

Tiam1-deficient mice developed very few skin tumours that grew very slowly compared to tumours of the wild-type mice. However, tumours arising in the Tiam1 KO mice progressed more frequently to malignancy (Malliri et al. Nature 2002). One mechanism by which TIAM1 and RAC suppress malignant progression is through promoting cell-cell adhesion. We identified β2-syntrophin, a component of the dystroglycan adhesion complex, as a TIAM1 binding partner. Our study (Mack et al. Nat Cell Biol. 2012) unearthed a novel role for this complex in promoting tight junction formation and the establishment of apicobasal polarity through the generation of a RAC activity gradient in the membrane region encompassing these junctions.

Malignant progression can entail the loss of cell-cell adhesion. Over-expression of activated RAC or TIAM1 promotes the formation of adherens junctions (AJs) and the accompanying induction of an epithelial-like phenotype in a number of mesenchymal cell lines (Malliri & Collard, Curr Opin Cell Biol 2003). Moreover, TIAM1 is required for both the formation as well as the maintenance of cadherin-based adhesions (Malliri et al. J Biol Chem 2004). The oncoprotein SRC, a non-receptor tyrosine kinase, targets AJs for disassembly. Previously, we showed that SRC phosphorylates TIAM1 inducing its cleavage by Calpain and its depletion from adherens junctions. Abrogating TIAM1 phosphorylation by SRC suppressed AJ disassembly (Woodcock et al. Mol Cell 2009). In a recent study from our laboratory (Vaughan et al. Cell Rep 2015), we found that TIAM1 is ubiquitylated and degraded upon treatment of cells with hepatocyte growth factor (HGF), a cytokine that is abundant in cancer and promotes invasion of cancer cells. We mapped the ubiquitylation site on TIAM1 and also identified the responsible E3 ligase as being the HECT family member HUWE1. Moreover, we showed that interfering with TIAM1 ubiquitylation by depleting HUWE1 or mutating the ubiquitylation site retards the scattering and invasion of cells through delaying AJ disassembly. HGF and HUWE1 are abundant in lung cancer. We showed that HUWE1 and TIAM1 expression are inversely correlated in lung cancer specimens and significantly that HUWE1 promotes lung cancer invasion by degrading TIAM1. Potentially, pharmacological agents capable of disrupting the HUWE1-TIAM1 interaction could antagonise invasion of lung and other cancer cells, reducing the risk of metastasis.