Role of IQGAP1 in Carcinogenesis

Tao, Wei; Lambert, Paul F.

doi:10.3390/cancers13163940

Cited by 36 publications

(28 citation statements)

References 180 publications

(311 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overexpression of ANLN also correlates with poorer prognosis in HNSCC patients. , Knocking down ANLN in HNSCC cell lines decreases HNSCC cell invasion and increases cell apoptosis. , Interestingly, ANLN interacts with several splicing factors, including SRSF4, SRSF6, and SRSF9. , In our NOKs data set, ANLN was significantly increased with the loss of IQGAP1 (up 1.8-fold). Additionally, the alternative spliced isoforms of ANLN contribute to HNSCC by regulating cell proliferation, migration, and invasion, which are activities regulated by IQGAP1. , Therefore, these recent studies raise the possibility that both ANLN and FANCI could be alternatively spliced genes regulated by IQGAP1 and contribute to HNSCC.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, the alternative spliced isoforms of ANLN contribute to HNSCC by regulating cell proliferation, migration, and invasion, which are activities regulated by IQGAP1. 102,103 Therefore, these recent studies raise the possibility that both ANLN and FANCI could be alternatively spliced genes regulated by IQGAP1 and contribute to HNSCC.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

See 1 more Smart Citation

IQGAP1 and RNA Splicing in the Context of Head and Neck via Phosphoproteomics

et al. 2022

Self Cite

View full text Add to dashboard Cite

IQGAP1 (IQ motif-containing GTPase-activating protein 1) scaffolds several signaling pathways in mammalian cells that are implicated in carcinogenesis, including the RAS and PI3K pathways that involve multiple protein kinases. IQGAP1 has been shown to promote head and neck squamous cell carcinoma (HNSCC); however, the underlying mechanism(s) remains unclear. Here, we report a mass spectrometry-based analysis identifying differences in phosphorylation of cellular proteins in vivo and in vitro in the presence or absence of IQGAP1. By comparing the esophageal phosphoproteome profiles between Iqgap1 +/+ and Iqgap1 −/− mice, we identified RNA splicing as one of the most altered cellular processes. Serine/arginine-rich splicing factor 6 (SRSF6) was the protein with the most downregulated levels of phosphorylation in Iqgap1 −/− tissue. We confirmed that the absence of IQGAP1 reduced SRSF6 phosphorylation both in vivo and in vitro. We then expanded our analysis to human normal oral keratinocytes. Again, we found factors involved in RNA splicing to be highly altered in the phosphoproteome profile upon genetic disruption of IQGAP1. Both the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Cancer Genome Atlas (TCGA) data sets indicate that phosphorylation of splicing-related proteins is important in HNSCC prognosis. The Biological General Repository for Interaction Datasets (BioGRID) repository also suggested multiple interactions between IQGAP1 and splicingrelated proteins. Based on these collective observations, we propose that IQGAP1 regulates the phosphorylation of splicing proteins, which potentially affects their splicing activities and, therefore, contributes to HNSCC. Raw data are available from the MassIVE database with identifier MSV000087770.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

IQGAP1 and RNA Splicing in the Context of Head and Neck via Phosphoproteomics

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…It has an evolutionarily ancient role in regulating cytoskeletal rearrangements in fungi and animals [62,63]. In mammals, it also functions as a scaffold protein for the RTK/RAS/MAPK pathway and the PI3K pathway -two of the pathways most frequently mutated in cancer [64][65][66] -and additionally regulates several other cancer-relevant signaling pathways [17][18][19][20][21]. Much work still needs to be done to understand how IQGAP1 and other scaffold proteins coordinate signaling in localized subcellular regions depending on cell type and cell context, how this may go awry in disease, and how it might be exploited for new targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

“…Signaling scaffold proteins -large, multidomain proteins that bind to multiple members of one or more signaling pathways -participate in numerous protein-protein interactions that could be targeted to disrupt signaling [7,[12][13][14][15][16]. Indeed, studies with human IQGAP1, a scaffold protein for multiple cancer-associated signaling pathways [17][18][19][20][21], have led to the discovery that its 27-residue WW domain, when engineered as a cell-penetrating peptide, shows broad anti-tumor activity with minimal associated toxicity [12,22].…”

Section: Introductionmentioning

confidence: 99%

The WW domain of IQGAP1 binds directly to the p110α catalytic subunit of PI 3-kinase

Bardwell

Paul²,

Yoneda

et al. 2022

Preprint

View full text Add to dashboard Cite

IQGAP1 is a multi-domain cancer-associated protein that serves as a scaffold protein for multiple signaling pathways. Numerous binding partners have been found for the calponin homology, IQ and GAP-related domains in IQGAP1. Identification of a binding partner for its WW domain has proven elusive, however, even though a cell-penetrating peptide derived from this domain has marked anti-tumor activity. Here, using in vitro binding assays with human proteins, we show that the WW domain of human IQGAP1 binds directly to the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K). In contrast, the WW domain does not bind to ERK1/2, MEK1/2, or the p85α regulatory subunit of PI3K when p85α is expressed alone. However, the WW domain is able to bind to the p110α/p85α heterodimer when both subunits are co-expressed, as well as to the mutationally activated p110α/p65α heterodimer. We present a model of the structure of the IQGAP1 WW domain, and experimentally identify key residues in the hydrophobic core and beta strands of the WW domain that are required for binding to p110α. These findings contribute to a more precise understanding of IQGAP1-mediated scaffolding, and of how IQGAP1-derived therapeutic peptides might inhibit tumorigenesis.

show abstract

“…They have been localized at multiple subcellular sites orchestrating different signaling pathways and thus controlling a variety of cellular functions [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Notably, IQGAP1 has been implicated as a drug target due to its vital regulatory roles in cancer development [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ] although the molecular mechanism of its functions is unclear.…”

Section: Introductionmentioning

confidence: 99%

CDC42-IQGAP Interactions Scrutinized: New Insights into the Binding Properties of the GAP-Related Domain

Mosaddeghzadeh

Pudewell

Bazgir

et al. 2022

IJMS

View full text Add to dashboard Cite

The IQ motif-containing GTPase-activating protein (IQGAP) family composes of three highly-related and evolutionarily conserved paralogs (IQGAP1, IQGAP2 and IQGAP3), which fine tune as scaffolding proteins numerous fundamental cellular processes. IQGAP1 is described as an effector of CDC42, although its effector function yet re-mains unclear. Biophysical, biochemical and molecular dynamic simulation studies have proposed that IQGAP RASGAP-related domains (GRDs) bind to the switch regions and the insert helix of CDC42 in a GTP-dependent manner. Our kinetic and equilibrium studies have shown that IQGAP1 GRD binds, in contrast to its C-terminal 794 amino acids (called C794), CDC42 in a nucleotide-independent manner indicating a binding outside the switch regions. To resolve this discrepancy and move beyond the one-sided view of GRD, we carried out affinity measurements and a systematic mutational analysis of the interfacing residues between GRD and CDC42 based on the crystal structure of the IQGAP2 GRD-CDC42Q61L GTP complex. We determined a 100-fold lower affinity of the GRD1 of IQGAP1 and of GRD2 of IQGAP2 for CDC42 mGppNHp in comparison to C794/C795 proteins. Moreover, partial and major mutation of CDC42 switch regions substantially affected C794/C795 binding but only a little GRD1 and remarkably not at all the GRD2 binding. However, we clearly showed that GRD2 contributes to the overall affinity of C795 by using a 11 amino acid mutated GRD variant. Furthermore, the GRD1 binding to the CDC42 was abolished using specific point mutations within the insert helix of CDC42 clearly supporting the notion that CDC42 binding site(s) of IQGAP GRD lies outside the switch regions among others in the insert helix. Collectively, this study provides further evidence for a mechanistic framework model that is based on a multi-step binding process, in which IQGAP GRD might act as a ‘scaffolding domain’ by binding CDC42 irrespective of its nucleotide-bound forms, followed by other IQGAP domains downstream of GRD that act as an effector domain and is in charge for a GTP-dependent interaction with CDC42.

show abstract

Role of IQGAP1 in Carcinogenesis

Cited by 36 publications

References 180 publications

IQGAP1 and RNA Splicing in the Context of Head and Neck via Phosphoproteomics

IQGAP1 and RNA Splicing in the Context of Head and Neck via Phosphoproteomics

The WW domain of IQGAP1 binds directly to the p110α catalytic subunit of PI 3-kinase

CDC42-IQGAP Interactions Scrutinized: New Insights into the Binding Properties of the GAP-Related Domain

Contact Info

Product

Resources

About