IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver
Chunsheng Liu, Daniel D. Billadeau, Haitham Abdelhakim, Edward Leof, Kozo Kaibuchi, Carmelo Bernabeu, George S. Bloom, Liu Yang, Lisa Boardman, Vijay H. Shah, Ningling Kang
Chunsheng Liu, Daniel D. Billadeau, Haitham Abdelhakim, Edward Leof, Kozo Kaibuchi, Carmelo Bernabeu, George S. Bloom, Liu Yang, Lisa Boardman, Vijay H. Shah, Ningling Kang
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Research Article Oncology

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

Abstract

In the tumor microenvironment, TGF-β induces transdifferentiation of quiescent pericytes and related stromal cells into myofibroblasts that promote tumor growth and metastasis. The mechanisms governing myofibroblastic activation remain poorly understood, and its role in the tumor microenvironment has not been explored. Here, we demonstrate that IQ motif containing GTPase activating protein 1 (IQGAP1) binds to TGF-β receptor II (TβRII) and suppresses TβRII-mediated signaling in pericytes to prevent myofibroblastic differentiation in the tumor microenvironment. We found that TGF-β1 recruited IQGAP1 to TβRII in hepatic stellate cells (HSCs), the resident liver pericytes. Iqgap1 knockdown inhibited the targeting of the E3 ubiquitin ligase SMAD ubiquitination regulatory factor 1 (SMURF1) to the plasma membrane and TβRII ubiquitination and degradation. Thus, Iqgap1 knockdown stabilized TβRII and potentiated TGF-β1 transdifferentiation of pericytes into myofibroblasts in vitro. Iqgap1 deficiency in HSCs promoted myofibroblast activation, tumor implantation, and metastatic growth in mice via upregulation of paracrine signaling molecules. Additionally, we found that IQGAP1 expression was downregulated in myofibroblasts associated with human colorectal liver metastases. Taken together, our studies demonstrate that IQGAP1 in the tumor microenvironment suppresses TβRII and TGF-β dependent myofibroblastic differentiation to constrain tumor growth.

Authors

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

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Figure 1

IQGAP1 interacts with TβRII and regulates its stability.

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IQGAP1 interacts with TβRII and regulates its stability. (A) Left: HSCs ...
(A) Left: HSCs that express TβRII-HA by retroviral transduction were transduced with lentiviruses encoding nontargeting shRNA (NT shRNA, control) or IQGAP1 shRNAs, and subjected to WB for TβRII. Knockdown of IQGAP1 by 3 different shRNAs consistently upregulated TβRII protein levels. Middle: cells were transduced with retroviruses encoding YFP (control) or IQGAP1-YFP. Overexpression of IQGAP in HSCs reduced TβRII protein. Right: endogenous TβRII protein levels increased in IQGAP1-knockdown cells. (B) HSCs transduced with lentiviruses encoding either NT shRNA or IQGAP1 shRNA were harvested for RNA extraction and SYBR green–based real-time RT-PCR. IQGAP1 knockdown did not change TβRII mRNA levels. n = 3 independent experiments. (C) IQGAP1 (red) and TβRII-HA (green) colocalized at the plasma membrane (arrowheads) and in intracellular vesicles (arrows) in HSCs by IF. Scale bars 20 μm. (D) Left: TβRII coprecipitated with IQGAP1 when IP was performed using anti-IQGAP1. Middle: IQGAP1 coprecipitated with TβRII-HA when IP was performed using anti-HA. Right: IQGAP1 coprecipitated with endogenous TβRII when IP was performed using anti-TβRII. Data are representative of multiple repeats with similar results.