IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver

Liu, Chunsheng; Billadeau, Daniel D.; Abdelhakim, Haitham; Leof, Edward B.; Kaibuchi, Kozo; Bernabeu, Carmelo; Bloom, George S.; Yang, Liu; Boardman, Lisa A.; Shah, Vijay H.; Kang, Ningling

doi:10.1172/jci63836

Cited by 84 publications

(155 citation statements)

References 59 publications

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“…tor 1 to IQGAP1 (18). Similarly, VEGF enhances the interaction of vascular endothelial growth factor receptor-2 with IQGAP1 in human umbilical vein endothelial cells (19), and transforming growth factor ␤-1 (TGF-␤1) increases the binding of IQGAP1 to TGF-␤ receptor II (34). In contrast to these data, we observed that E 2 significantly attenuated the interaction between IQGAP1 and ER␣ in cells.…”

Section: Discussioncontrasting

confidence: 66%

IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

Erdemir¹,

Sacks

2014

Journal of Biological Chemistry

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Background: IQGAP1 is a scaffold protein that modulates diverse signaling pathways. Results: IQGAP1 binds to estrogen receptor-␣ (ER␣) and ER␤, and knockdown of IQGAP1 impairs 17␤-estradiol (E 2 )-stimulated transcriptional activation in human breast epithelial cells. Conclusion: IQGAP1 modulates ER␣ function and is required for maximal E 2 function. Significance: IQGAP1 might be a therapeutic target for patients with breast carcinoma.

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Section: Discussioncontrasting

confidence: 66%

IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

Erdemir¹,

Sacks

2014

Journal of Biological Chemistry

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“…In addition, TP53, IKBKB, TGFB1 and TGFBR2 are strongly associated with EMT (p = 9.0 × 10 −6 , Fisher’s exact test). A literature search revealed that IQGAP1 has been shown to bind TGFBR2, following TGF-β stimulation, which promotes SMURF1 association with TGFBR2 and subsequent ubiquitination/degradation of the receptor (30). Additionally, dysregulated TGF-β signaling has been shown to be pro-oncogenic (31).…”

Section: Resultsmentioning

confidence: 99%

Patient Mutation Directed shRNA Screen Uncovers Novel Bladder Tumor Growth Suppressors

Hensel¹,

Duex²,

Owens³

et al. 2015

Molecular Cancer Research

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Next generation sequencing (NGS) of human bladder cancer has revealed many gene alterations compared with normal tissue, with most being predicted to be “loss of function”. However, given the high number of alterations, evaluating the functional impact of each is impractical. Here we develop and use a high-throughput, in vivo strategy to determine which alterations are loss of function in tumor growth suppressors. Genes reported as altered by NGS in bladder cancer patients were bioinformatically processed by MutationTaster and MutationAssessor, with 283 predicted as loss of function. A shRNA lentiviral library targeting these genes was transduced into T24 cells, a non-tumorigenic human bladder cancer cell line, followed by injection into mice. Tumors that arose were sequenced and the dominant shRNA constructs were found to target IQGAP1, SAMD9L, PCIF1, MED1 and KATNAL1 genes. In vitro validation experiments revealed that shRNA molecules directed at IQGAP1 showed the most profound increase in anchorage-independent growth of T24 cells. The clinical relevance of IQGAP1 as a tumor growth suppressor is supported by the finding that its expression is lower in bladder cancer compared with benign patient urothelium in multiple independent datasets. Lower IQGAP1 protein expression associated with higher tumor grade and decreased patient survival. Finally, depletion of IQGAP1 leads to increased TGFBR2 with TGFβ signaling, explaining in part how reduced IQGAP1 promotes tumor growth. These findings suggest IQGAP1 is a bladder tumor growth suppressor that works via modulating TGFβ signaling and is a potentially clinically useful biomarker. Implications This study used gene mutation information from patient-derived bladder tumor specimens to inform the development of a screen used to identify novel tumor growth suppressors. This included identification of the protein IQGAP1 as a potent bladder cancer growth suppressor.

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“…Biotinylation Assay for Plasma Membrane Integrin ActivityBiotin-based assays were performed as described previously (22,30). HSCs were fasted overnight and treated with exosome for 15 min.…”

Section: Methodsmentioning

confidence: 99%

Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration

Wang

Ding

Yaqoob

et al. 2015

Journal of Biological Chemistry

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188

172

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Exosomes are cell-derived extracellular vesicles thought to promote intercellular communication by delivering specific content to target cells. The aim of this study was to determine whether endothelial cell (EC)-derived exosomes could regulate the phenotype of hepatic stellate cells (HSCs). Initial microarray studies showed that fibroblast growth factor 2 induced a 2.4-fold increase in mRNA levels of sphingosine kinase 1 (SK1). Exosomes derived from an SK1-overexpressing EC line increased HSC migration 3.2-fold. Migration was not conferred by the dominant negative SK1 exosome. Incubation of HSCs with exosomes was also associated with an 8.3-fold increase in phosphorylation of AKT and 2.5-fold increase in migration. Exosomes were found to express the matrix protein and integrin ligand fibronectin (FN) by Western blot analysis and transmission electron microscopy. Blockade of the FN-integrin interaction with a CD29 neutralizing antibody or the RGD peptide attenuated exosome-induced HSC AKT phosphorylation and migration. Inhibition of endocytosis with transfection of dynamin siRNA, the dominant negative dynamin GTPase construct Dyn2K44A, or the pharmacological inhibitor Dynasore significantly attenuated exosome-induced AKT phosphorylation. SK1 levels were increased in serum exosomes derived from mice with experimental liver fibrosis, and SK1 mRNA levels were up-regulated 2.5-fold in human liver cirrhosis patient samples. Finally, S1PR2 inhibition protected mice from CCl 4 -induced liver fibrosis. Therefore, EC-derived SK1-containing exosomes regulate HSC signaling and migration through FNintegrin-dependent exosome adherence and dynamin-dependent exosome internalization. These findings advance our understanding of EC/HSC cross-talk and identify exosomes as a potential target to attenuate pathobiology signals.

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IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver

Cited by 84 publications

References 59 publications

IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

Patient Mutation Directed shRNA Screen Uncovers Novel Bladder Tumor Growth Suppressors

Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration

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