Ras GAP-related and C-terminal domain-dependent localization and tumorigenic activities of IQGAP1 in melanoma cells

Reimer, Michael; Denby, Elisabeth; Zustiak, Silviya Petrova; Schober, Joseph

doi:10.1371/journal.pone.0189589

Cited by 8 publications

(5 citation statements)

References 54 publications

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“…We hypothesize that the acceleration of melanoma progression we observe in tumors expressing CDK13 mel could be influenced by the presence of these aberrant truncated proteins. Some of the proteins showing evidence of truncation in our data are tumor suppressors that would be expected to lose functionality; others may act in a dominant negative fashion to favor tumor progression 29–31 .…”

Section: Discussionmentioning

confidence: 83%

“…Several of the truncated proteins we identified are predicted to lose carboxy-terminal enzymatic domains, including Ilk, Crk, Ikbkb, and Cdk15 (Figure 4B-E). Ilk, Crk, and Ikbkb have published evidence of dominant negative activity upon carboxy-terminal loss 29–31 . Individual impacted proteins showed an increase in truncated species at the expense of full-length proteins in CDK13 mel zebrafish melanomas.…”

Section: Resultsmentioning

confidence: 99%

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CDK13 Mutations Drive Melanoma via Accumulation of Prematurely Terminated Transcripts

et al. 2019

Preprint

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23As CDK13 mel acts via a dominant negative mechanism and no CDK13 mel mutations are 126 observed in the Cyclin binding domain, we hypothesized that Cyclin binding is required for 127 CDK13 mel dominant negative activity. To test whether the canonical CDK13 Cyclin, 128 CCNK 18,22,23 , or the related CCNT1 are required for CDK13 mel dominant negative 129 melanomagenesis in vivo, we co-injected vectors that express melanocyte-specific CDK13 mel and 130 melanocyte-specific CRISPR of ccnK or ccnT1 in the mitfa -/-; BRAF; p53 -/zebrafish melanoma 131 model. ccnK melanocyte-specific CRISPR expedited melanoma in the presence of CDK13 W878L , 132 but not alone ( Figure S1L-M). ccnT1 melanocyte-specific CRISPR suppressed CDK13 W878L and 133 CDK13 R860Q oncogenesis but had no effect by itself ( Figure 1K-L, S1O). PCR across the 134 CRISPR cut site confirmed indels directed by the ccnT1, ccnK, and control gRNAs (Figure 135 S1N). These data indicate that CDK13 mel oncogenesis requires CCNT1 for its dominant negative 136 oncogenic activity. 137 Mutant CDK13 binds chromatin in a dominant negative manner. 138As CDK13 is localized in the nucleus 24 and CDK13 WT can phosphorylate the RNAPII 139

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Section: Discussionmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

CDK13 Mutations Drive Melanoma via Accumulation of Prematurely Terminated Transcripts

et al. 2019

Preprint

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“…However, observations of negative regulatory behaviors have also been reported. For example, IQGAP1 has been shown to colocalize with Arp2/3 at the protruding edges of certain types of migrating cells but binds to retracting edge regions that have lost Arp3 signals in other cells (23). Conflicting positive and negative regulatory behaviors have also been found in IQGAP1 knockdown via RNA interference, which has been shown to reduce actin-driven membrane ruffling in lamellipodia ( 22) but appears to upregulate actin polymerization in other settings, including the formation of the T-cell immunological synapse (24).…”

Section: Discussionmentioning

confidence: 99%

“…Although IQGAP1 does not function as a traditional GTPase activating protein (GAP), it has been shown to bind Cdc42 and Rac1 via multistep, nucleotide-dependent binding mechanisms involving the GRD and RGCT domains (20). These interactions have been implicated in mechanisms that regulate Arp2/ 3-mediated actin polymerization in lamellipodia and specialized cell-cell interfaces such as the immunological synapse, although there is conflicting evidence as to whether IQGAP1 regulates actin positively or negatively (21)(22)(23)(24). IQGAP1 has also recently been reported to assemble multiple PI kinase complexes to facilitate multistep PI synthesis and PI3K/ PIP 3 signaling.…”

Section: Introductionmentioning

confidence: 99%

Membrane and Actin Tethering Transitions Help IQGAP1 Coordinate GTPase and Lipid Messenger Signaling

Trenton

McLaughlin

Bellamkonda

et al. 2020

Biophysical Journal

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The coordination of lipid messenger signaling with cytoskeletal regulation is central to many organelle-specific regulatory processes. This coupling often depends on the function of multidomain scaffolds that orchestrate transient interactions among multiple signaling intermediates and regulatory proteins on organelles. The number of possible scaffold interaction partners and the ability for these interactions to occur at different timescales makes investigations of scaffold functions challenging. This work employs live cell imaging to probe how the multidomain scaffold IQ motif containing GTPase activating protein 1 (IQGAP1) coordinates the activities of proteins affecting local actin polymerization, membrane processing, and phosphoinositide signaling. Using endosomes that are confined by a local actin network as a model system, we demonstrate that IQGAP1 can transition between different actin and endosomal membrane tethered states. Fast scaffold binding/disassociation transitions are shown to be driven by interactions between C-terminal scaffold domains and Rho GTPases at the membrane. Fluctuations in these binding modes are linked to negative regulation of actin polymerization. Although this control governs core elements of IQGAP1 dynamics, actin binding by the N-terminal calponin homology domain of the scaffold is shown to help the scaffold track the temporal development of endosome membrane markers, implying actin associations bolster membrane and actin coordination. Importantly, these effects are not easily distilled purely through standard (static) co-localization analyses or traditional pathway perturbations methods and were resolved by performing dynamic correlation and multiple regression analyses of IQGAP1 scaffold mutants. Using these capabilities with pharmacological inhibition, we provide evidence that membrane tethering is dependent on the activities of the lipid kinase phosphoinositide 3-kinase in addition to the Rho GTPases Rac1 and Cdc42. Overall, these methods and results point to a scaffold tethering mechanism that allows IQGAP1 to help control the amplitude of phosphoinositide lipid messenger signaling by coordinating signaling intermediate activities with the development and disassembly of local actin cytoskeletal networks.

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“…Nrf2 (nuclear factor erythroid 2-related factor 2) enhances mutant K-ras/p53-driven pancreatic carcinogenesis [2] . Ras GAP (guanine-activating proteins)-related and C-terminal domain-dependent localization (and carcinogenic activities due to the scaffolding factor IQGAP1 that is involved in cell-cell adhesion, polarity and motility in melanoma cells) play a role in actin cytoskeleton dynamics during membrane ruffling and lamelliopodium protrusion [3] . It is further to such considerations that intra-cellular localization contrasts with a global series of roles of RAS in cell differentiation and growth-modulation.…”

Section: Introductionmentioning

confidence: 99%

Proponent Specificity as Targeting Evolutionary Traits in Ras Isoform Mutability in Carcinogenesis

2018

Med One

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Distributional and re-distributional patterns of compartmentalization of RAS isoforms are core, persistently active abnormalities that are central/additional phenomena within mutable molecular structure and dysfunction in carcinogenesis. In such terms, ongoing transformations attributes, both within the plasmalemma and the internal membrane compartments, potentiate transformation, as further illustrated by sequestration of mutational forms of RAS. The incremental adaptation response of injured cells further conforms with the resultant dimensions of cooperating networks, rather than as linear pathways; these network organizations induce groups of neoplastic cells to further augment the effector end-target predispositions toward pre-carcinogenesis and carcinogenesis. RAS formulation is hence primarily an effector initiator and maintenance-inducing role-pattern formulator in carcinogenesis, as reflected in central metabolic pathways of cell growth promotion and proliferation.

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Ras GAP-related and C-terminal domain-dependent localization and tumorigenic activities of IQGAP1 in melanoma cells

Cited by 8 publications

References 54 publications

CDK13 Mutations Drive Melanoma via Accumulation of Prematurely Terminated Transcripts

CDK13 Mutations Drive Melanoma via Accumulation of Prematurely Terminated Transcripts

Membrane and Actin Tethering Transitions Help IQGAP1 Coordinate GTPase and Lipid Messenger Signaling

Proponent Specificity as Targeting Evolutionary Traits in Ras Isoform Mutability in Carcinogenesis

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