Advances and Insights of APC-Asef Inhibitors for Metastatic Colorectal Cancer Therapy

In Colorectal cancer (CRC), adenomatous polyposis coli (APC) directly interacts with the Rho guanine nucleotide exchange factor 4 (Asef) and releases its GEF activity. Activated Asef promotes the aberrant migration and invasion of CRC cell through a CDC42-mediated pathway. Knockdown of either APC or Asef significantly decreases the migration of CRC cells. Therefore, disrupting the APC-Asef interaction is a promising strategy for the treatment of invasive CRC. With the growth of structural information, APC-Asef inhibitors have been designed, providing hope for CRC therapy. Here, we will review the APC-Asef interaction in cancer biology, the structural complex of APC-Asef, two generations of peptide inhibitors of APC-Asef, and small molecule inhibitors of APC-Asef, focusing on research articles over the past 30 years. We posit that these advances in the discovery of APC-Asef inhibitors establish the protein-protein interaction (PPI) as targetable and provide a framework for other PPI programs.

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Long Non-Coding RNA LINC00355 Promotes the Development and Progression of Colorectal Cancer by Elevating Guanine Nucleotide Exchange Factor T Expression via RNA Binding Protein lin-28 Homolog A

Frontiers in Oncology ◽

10.3389/fonc.2020.582669 ◽

2020 ◽

Vol 10 ◽

Author(s):

Yuanyuan Wang ◽

Bing Zhang ◽

Ge Gao ◽

Yinping Zhang ◽

Qingxin Xia

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Mrna Stability ◽

Guanine Nucleotide Exchange Factor ◽

Regulatory Mechanisms ◽

Migration And Invasion ◽

Guanine Nucleotide ◽

Nucleotide Exchange ◽

Guanine Nucleotide Exchange ◽

Nucleotide Exchange Factor

BackgroundOur previous study showed that guanine nucleotide exchange factor T (GEFT) was highly expressed in colorectal cancer (CRC) tissues and CRC patients with high GEFT expression had a poor prognosis, and suggested the close link of GEFT expression and CRC tumorigenesis/metastasis. In this text, the roles and upstream regulatory mechanisms of GEFT in the development and progression of CRC were further investigated.MethodsExpression levels of GEFT mRNA and LINC00355 was measured by RT-qPCR assay. Protein levels of lin-28 homologue A (LIN28A) and GEFT were determined by western blot assay. Cell proliferative, migratory, and invasive capacities were assessed by CCK-8, Transwell migration and invasion assays, respectively. The effect of GEFT knockdown on CRC tumorigenesis was examined by mouse xenograft experiments in vivo. GEFT mRNA stability was examined by actinomycin D assay. The relationships of LINC000355, LIN28A, and GEFT were explored by RNA pull down and RIP assays.ResultsGEFT was highly expressed in CRC tissues and cell lines. GEFT knockdown inhibited CRC cell proliferation, migration, and invasion, and hindered CRC xenograft tumor growth. GEFT overexpression alleviated the detrimental effects of LINC00355 loss on CRC cell proliferation, migration, and invasion. LINC00355 promoted GEFT expression and enhanced GEFT mRNA stability via LIN28A. LIN28A knockdown weakened the promotive effect of LINC00355 on CRC cell proliferation, migration, and invasion.ConclusionLINC00355 facilitated CRC tumorigenesis and progression by increasing GEFT expression via LIN28A, deepening our understanding on roles and upstream regulatory mechanisms of GEFT in CRC development and progression.

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The Src Homology 3 Domain-containing Guanine Nucleotide Exchange Factor Is Overexpressed in High-grade Gliomas and Promotes Tumor Necrosis Factor-like Weak Inducer of Apoptosis-Fibroblast Growth Factor-inducible 14-induced Cell Migration and Invasion via Tumor Necrosis Factor Receptor-associated Factor 2

Journal of Biological Chemistry ◽

10.1074/jbc.m113.468686 ◽

2013 ◽

Vol 288 (30) ◽

pp. 21887-21897 ◽

Cited By ~ 19

Author(s):

Shannon P. Fortin Ensign ◽

Ian T. Mathews ◽

Jennifer M. Eschbacher ◽

Joseph C. Loftus ◽

Marc H. Symons ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Migration And Invasion ◽

Nucleotide Exchange ◽

Src Homology 3 ◽

Guanine Nucleotide Exchange ◽

Nucleotide Exchange Factor ◽

Src Homology ◽

Necrosis Factor

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C3G Protein, a New Player in Glioblastoma

International Journal of Molecular Sciences ◽

10.3390/ijms221810018 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10018

Author(s):

Sara Manzano ◽

Alvaro Gutierrez-Uzquiza ◽

Paloma Bragado ◽

Angel M Cuesta ◽

Carmen Guerrero ◽

...

Keyword(s):

Tyrosine Kinases ◽

Protein A ◽

Patient Treatment ◽

Migration And Invasion ◽

Nucleotide Exchange ◽

Cellular Functions ◽

Mesenchymal Phenotype ◽

Guanine Nucleotide Exchange ◽

Nucleotide Exchange Factor ◽

Personalised Treatment

C3G (RAPGEF1) is a guanine nucleotide exchange factor (GEF) for GTPases from the Ras superfamily, mainly Rap1, although it also acts through GEF-independent mechanisms. C3G regulates several cellular functions. It is expressed at relatively high levels in specific brain areas, playing important roles during embryonic development. Recent studies have uncovered different roles for C3G in cancer that are likely to depend on cell context, tumour type, and stage. However, its role in brain tumours remained unknown until very recently. We found that C3G expression is downregulated in GBM, which promotes the acquisition of a more mesenchymal phenotype, enhancing migration and invasion, but not proliferation. ERKs hyperactivation, likely induced by FGFR1, is responsible for this pro-invasive effect detected in C3G silenced cells. Other RTKs (Receptor Tyrosine Kinases) are also dysregulated and could also contribute to C3G effects. However, it remains undetermined whether Rap1 is a mediator of C3G actions in GBM. Various Rap1 isoforms can promote proliferation and invasion in GBM cells, while C3G inhibits migration/invasion. Therefore, other RapGEFs could play a major role regulating Rap1 activity in these tumours. Based on the information available, C3G could represent a new biomarker for GBM diagnosis, prognosis, and personalised treatment of patients in combination with other GBM molecular markers. The quantification of C3G levels in circulating tumour cells (CTCs) in the cerebrospinal liquid and/or circulating fluids might be a useful tool to improve GBM patient treatment and survival.

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A NUMB–EFA6B–ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility

The Journal of Cell Biology ◽

10.1083/jcb.201802023 ◽

2018 ◽

Vol 217 (9) ◽

pp. 3161-3182 ◽

Cited By ~ 6

Author(s):

Martina Zobel ◽

Andrea Disanza ◽

Francesca Senic-Matuglia ◽

Michel Franco ◽

Ivan Nicola Colaluca ◽

...

Keyword(s):

Molecular Mechanisms ◽

Negative Regulator ◽

Migration And Invasion ◽

Nucleotide Exchange ◽

Cellular Processes ◽

Guanine Nucleotide Exchange ◽

Nucleotide Exchange Factor ◽

Endocytic Protein ◽

Membrane Protrusions

The endocytic protein NUMB has been implicated in the control of various polarized cellular processes, including the acquisition of mesenchymal migratory traits through molecular mechanisms that have only been partially defined. Here, we report that NUMB is a negative regulator of a specialized set of understudied, apically restricted, actin-based protrusions, the circular dorsal ruffles (CDRs), induced by either PDGF or HGF stimulation. Through its PTB domain, NUMB binds directly to an N-terminal NPLF motif of the ARF6 guanine nucleotide exchange factor, EFA6B, and promotes its exchange activity in vitro. In cells, a NUMB–EFA6B–ARF6 axis regulates the recycling of the actin regulatory cargo RAC1 and is critical for the formation of CDRs that mark the acquisition of a mesenchymal mode of motility. Consistently, loss of NUMB promotes HGF-induced cell migration and invasion. Thus, NUMB negatively controls membrane protrusions and the acquisition of mesenchymal migratory traits by modulating EFA6B–ARF6 activity.

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