About

Aberrant regulation of RAS, RHO and heterotrimeric GTPases is linked to a variety of disease states, including cancer, cardiovascular and neurological disorders. Our lab employs multidisciplinary structural, computational, biophysical, biochemical and cell biology approaches to elucidate how these GTPases recognize regulatory proteins and down stream effector targets, how mutations and posttranslational modifications alter GTPase function, and identify and characterize inhibitors that antagonize aberrant GTPase function in disease.

Research topics

• Medicine
• Biology
• Internal medicine
• Emergency medicine
• Cell biology
• Biochemistry
• Biophysics
• Demography
• Genetics
• Virology
• Pathology
• Cancer research

Selected publications

• Abstract 6944: Transient pan-RAF inhibitor treatment for melanoma prevention

  Cancer Research · 2025-04-21

  article

  Abstract Therapeutic options are currently limited for the 15-25% of cutaneous melanomas driven by an oncogenic NRAS mutation. Our previous findings showed that melanoma-associated NRAS substitutions stabilize conformations optimal for BRAF binding, thereby promoting RAF dimerization, proliferative signaling, and ultimately melanomagenesis. Building on these discoveries, we hypothesized that NRAS-mutant melanoma precursors would exhibit substitution-specific sensitivity to pan-RAF inhibition, and that a temporary blockade of RAF signaling would eliminate NRAS mutant-melanocytes in the skin. BRET and NanoBiT complementation assays revealed that pan-RAF inhibitors promote RAS-RAF and RAF-RAF interactions at lower doses in human melanoma cell lines with a weakly melanomagenic NRAS substitution (Q61H) compared to those with a stronger melanomagenic NRAS substitution (Q61R). Surprisingly, these drug-induced RAF complexes were associated with decreased MAPK>ERK signaling and higher drug sensitivity, suggesting that fully inhibited, drug-bound protomers drive increases in NRAS-RAF interactions. To test the mutation-specific sensitivity of NRAS-mutant melanoma precursors in vivo, mouse models of spontaneous NRAS Q61R- or Q61H-driven melanoma were prophylactically treated with a pan-RAF inhibitor for three days and then followed for tumor formation. Consistent with our in vitro data, short-term pan-RAF inhibitor treatment delayed melanoma onset in NRAS Q61H, but not Q61R mice. These findings highlight the critical role of RAF signaling in NRAS-mutant melanoma formation, suggesting that short-term use of effective, targeted therapies could prevent melanoma formation. Citation Format: Rachel E. Lew, Harsha S. Sanaka, Venkat R. Chirasani, Sharon L. Campbell, Christin E. Burd. Transient pan-RAF inhibitor treatment for melanoma prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6944.

  PublisherDOI

• Retention in Outpatient Psychological Treatment Services for Gambling: A Retrospective Cohort Analysis of Real-World Data Over a 10-Year Period

  International Journal of Mental Health and Addiction · 2025-11-10 · 2 citations

  articleOpen access

  Abstract Retention is a persistent challenge in gambling treatment services, yet studies utilising real-world data remain scarce. This study examined rates, reasons, and predictors of treatment attendance using a large dataset ( n = 18,642) from outpatient gambling services in New Zealand (2014–2023). Out of every three clients in this study, one attended a single session (27.7%), one attended ‘multiple sessions’ (between two and five: 35.5%), and one attended a ‘longer course’ of six or more sessions (36.8%). Some clients attended single or multiple sessions as they had completed treatment (23.7%–38.8%), highlighting that lower attendance can reflect positive outcomes. Factors associated with single or multiple session attendance included younger age, male gender, lower perceived gambling control, and higher gambling expenditure, while greater problem gambling severity, depressive symptoms, and suicidality were associated with a longer treatment course. The findings underscore the need for tailored retention strategies, particularly early in treatment, such as brief motivational interventions.

  PublisherOA PDFDOI

• Vinculin and metavinculin exhibit distinct effects on focal adhesion properties, cell migration, and mechanotransduction

  UNC Libraries · 2025-01-17 · 1 citations

  articleOpen access

  Vinculin (Vcn) is a ubiquitously expressed cytoskeletal protein that links transmembrane receptors to actin filaments, and plays a key role in regulating cell adhesion, motility, and force transmission. Metavinculin (MVcn) is a Vcn splice isoform that contains an additional exon encoding a 68-residue insert within the actin binding tail domain. MVcn is selectively expressed at sub-stoichiometic amounts relative to Vcn in smooth and cardiac muscle cells. Mutations in the MVcn insert are linked to various cardiomyopathies. In vitro analysis has previously shown that while both proteins can engage filamentous (F)-actin, only Vcn can promote F-actin bundling. Moreover, we and others have shown that MVcn can negatively regulate Vcn-mediated F-actin bundling in vitro. To investigate functional differences between MVcn and Vcn, we stably expressed either Vcn or MVcn in Vcn-null mouse embryonic fibroblasts. While both MVcn and Vcn were observed at FAs, MVcn-expressing cells had larger but fewer focal adhesions per cell compared to Vcn-expressing cells. MVcn-expressing cells migrated faster and exhibited greater persistence compared to Vcn-expressing cells, even though Vcn-containing FAs assembled and disassembled faster. Magnetic tweezer measurements on Vcn-expressing cells show a typical cell stiffening phenotype in response to externally applied force; however, this was absent in Vcn-null and MVcn-expressing cells. Our findings that MVcn expression leads to larger but fewer FAs per cell, in conjunction with the inability of MVcn to bundle F-actin in vitro and rescue the cell stiffening response, are consistent with our previous findings of actin bundling deficient Vcn variants, suggesting that deficient actin-bundling may account for some of the differences between Vcn and MVcn.

  PublisherDOI

• Oxidation of KRASG12C Effects Covalent Inhibitor Engagement and Therapeutic Response in Non-Small Cell Lung Cancer

  Free Radical Biology and Medicine · 2025-10-30

  article
  PublisherDOI

• Molecular basis for differential PIP2-mediated association between vinculin and its splice isoform metavinculin

  Journal of Biological Chemistry · 2025-05-14

  articleOpen accessSenior author

  <h2>Abstract</h2> Vinculin (Vcn) and its splice variant metavinculin (MVcn) are cell adhesion proteins that regulate cell morphology, adhesion and motility. They function as scaffold proteins that anchor membrane receptors to filamentous actin (F-actin) at focal adhesions (FA) and cell-cell junctions. MVcn bears an extra 68 amino acid insert in the tail domain and is selectively expressed in cardiac and smooth muscle cells at sub-stoichiometric levels relative to Vcn. Mutations in the MVcn tail domain (MVt) promote cardiomyopathy, yet how these mutations alter ligand interactions to promote defects in force transduction and reduced blood flow is unclear. One difference between Vcn and MVcn lies in the ability to reorganize F-actin, with MVcn negatively regulating Vcn-mediated F-actin bundling. Vcn associates with phosphatidylinositol 4,5-bisphosphate (PIP₂) through its tail domain (Vt) to drive recruitment, activation and FA turnover. However, it remains unclear whether MVcn specifically associates with PIP₂-containing membranes and how such interactions might influence its functional interplay with Vcn in tissues where both isoforms coexist. To evaluate the interaction of MVt and MVt cardiomyopathy mutants with PIP₂-membranes in comparison with Vt, we conducted mutagenesis, phospholipid-association assays and computational modeling. We found that MVt shows reduced association for PIP₂-containing liposomes relative to Vt due to sequence differences within the insert region. Moreover, mutations in MVt that promote cardiomyopathies do not affect PIP₂-dependent lipid association. These findings suggest that MVcn differs from Vcn in driving PIP₂-mediated membrane association and sheds light on the coordinate role of Vcn and MVcn in membrane association as well as MVcn cardiomyopathy defects.

  PublisherOA PDFDOI

• Molecular and functional profiling of Gαi as an intracellular pH sensor

  Nature Communications · 2025-04-11 · 2 citations

  articleOpen accessSenior author

  Heterotrimeric G proteins (Gα, Gβ and Gγ) act downstream of G-protein-coupled receptors (GPCRs) to mediate signaling pathways that regulate various physiological processes and human disease conditions. While human Gαi and its yeast homolog Gpa1 were previously postulated to function as intracellular pH sensors, the pH-sensing capabilities of Gαi and the underlying mechanism remain to be established. Our research shows that variations in pH significantly affect the structure and stability of Gαi-GDP. Specifically, at the lower end of the physiological pH range, the protein undergoes an order-to-disorder transition due to the loss of electrostatic interactions within the Gαi Switch regions, resulting in a reduction in agonist-mediated Gαi-Gβγ release. Further, we identified key residues within the Gαi Switch regions that form the pH-sensing network. Mutation of these residues in Gαi gives rise to 'low pH mimetics' that abolish pH-dependent thermostability changes and reduce Gαi-Gβγ release. Overall, our findings suggest that pH-sensitive structural changes in Gαi impact the agonist-mediated dissociation of Gβγ, which is essential for proper signaling.

  PublisherDOI

• Understanding dropout during psychological treatment for gambling: A scoping review

  Clinical Psychology Review · 2025-10-06 · 4 citations

  reviewOpen access

  Abstract This scoping review broadly aims to identify recent research on six indices of dropout during face-to-face psychological treatment for harmful gambling, including definitions of dropout, estimates of dropout, reasons for dropout, predictors of dropout, consequences of dropout, and solutions to dropout. A systematic search of electronic databases and grey literature identified 66 studies (from 67 articles/reports) published from 2004, most commonly contributing data to estimates (94 %), followed by predictors (74 %), definitions (73 %), reasons (15 %), consequences (8 %), and solutions (3 %). The findings revealed several definitions of dropout, typically relating to the non-attendance of a pre-defined and usually arbitrary number of treatment sessions, which risks the misclassification of clients with symptom improvement. The median rate of dropout (derived from 76 estimates) was 35.4 % across all treatment types and 34.8 % across Cognitive Behaviour Therapy (CBT) treatments. The most reported reasons for dropout were practical issues (e.g., scheduling conflicts), with few reasons relating to specific therapeutic orientations recorded. A large number of potential predictors have been examined with few consistent results, whereby being married/de-facto appears to consistently lower the risk of dropout. Dropout was consistently associated with higher subsequent gambling symptoms, urges, cognitions, and behaviors, with some additional evidence for worsened psychological symptoms, albeit based on a small number of studies. Only two studies examined the addition of motivational procedures to redress the risk of dropout, which produced favourable results. More research is needed, utilising standardised definitions and bespoke large-scale examinations, to improve retention during gambling treatment. • Broad review of research on dropout during face-to-face psychological treatment for gambling. • Dropout typically defined by non-attendance of arbitrary number of treatment sessions. • Median rate of dropout (across 76 estimates) was 35.4 % across treatment types. • Married/de-facto status consistently predicted dropout; dropout predicted worsened gambling. • Lack of research on solutions to dropout; some evidence for motivational techniques

  PublisherDOI

• Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation

  UNC Libraries · 2024-08-30

  articleOpen access
  PublisherDOI

• 7288 A Preclinical Mouse Model of Gender-Affirming Hormone Therapy: Metabolic and Behavioral Outcomes

  Journal of the Endocrine Society · 2024-10-01

  articleOpen access

  Abstract Disclosure: A. Yasrebi: None. K. Otersen: None. O. Groh: None. E. Guthman: None. I. Shmarakov: None. S. Campbell: None. T.A. Roepke: None. The long-term metabolic effects of gender-affirming hormone therapy (GAHT) is largely unknown, in part, due to the lack of properly designed preclinical animal models. Here we propose a rodent study design, beyond the classical endocrine model of gonadectomy and steroid treatment, to accurately reflect the reality of the trans experience. Specifically, trans women do not all seek or undergo orchidectomy (ORX) instead take estrogen supplementation along with an androgen blocker such as finasteride. In this study, 40 WT C57 male mice were divided into 4 groups of 10 mice - 1) intact with oil vehicle, 2) intact with estradiol benzoate (EB, 150 μg/kg/d) and finasteride (F, 0.25 mg/kg/d), 3) ORX with oil; and ORX with EB (150 μg/kg/d). Each mouse was dosed daily for 8 weeks while on a standard chow diet. Mice were pair housed and food intake and body weight were collected weekly prior to behavioral (open field, elevated plus, Y-maze) and metabolic (body composition, metabolic rates, activity, tolerance testing) phenotyping. Intact mice treated with EB+F exhibited less avoidance behaviors, potentially due to differences in movement, with no differences between treatments in the Y-maze. Cumulatively, Intact:EB+F gained less weight than Intact:oil (3.4 ± 0.4 g vs 5.3 ± 0.4 g), while ORX:oil mice gained less than ORX:EB (2.2 ± 0.5 g vs 5.5 ± 0.7 g). These interactive effects were due to differences in the gain of fat or lean mass between ORX and intact and lower cumulative food intake in ORX:oil mice (136 ± 3.8 g vs Intact:oil: 159 ± 4.9 g; Intact:EB+F: 167 ± 6.1 g; ORX:EB: 171 ± 3.4 g). Metabolic assessments found that Intact:EB+F exhibited elevated V.O2, V.CO2, and heat production in the light and dark cycle compared to Intact:oil, while ORX:EB only exhibited elevated heat production compared to ORX:oil. Similarly, Intact:EB+F and ORX:EB moved more than their counterparts during the dark cycle; however, only Intact:EB+F exhibited elevated wheel running. Tolerance tests (i.p.) found that glucose clearance was augmented in ORX:EB mice while insulin-induced glucose clearance was lower in Intact:EB+F compared to Intact:oil but modestly elevated by EB in ORX mice. These data, along with suppressed fasting blood glucose in ORX:EB mice, suggest that glucose homeostasis is differentially modulated by GAHT paradigms in mice. Analysis of hypothalamic, hepatic, adipose, and intestinal gene expression is currently underway. Collectively, these data, generated by using a translationally-relevant preclinical animal model, are the first to establish that metabolism is differentially affected by both steroid treatments and ORX and suggesting that the long-term metabolic effects of GAHT are dependent on the type of treatment. The underlying mechanisms and sites of action remain to be investigated. Presentation: 6/3/2024

  PublisherDOI

• Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer

  UNC Libraries · 2024-08-28 · 1 citations

  articleOpen access

  Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V- but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. SIGNIFICANCE: We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers.See related commentary by Falcomatà et al., p. 23.This article is highlighted in the In This Issue feature, p. 1.

  PublisherDOI

Recent grants

• NIH Grant R01GM080568

  NIH · $1.3M · 2014

• NIH Grant F32GM011847

  NIH · $31k

• Structure and Mechanism of G-proteins and cell adhesion proteins in regulation of cell growth and motility

  NIH · $4.2M · 2020–2030

• NIH Grant R01CA070308

  NIH · $1.1M · 2002

• NIH Grant R01GM081764

  NIH · $222k · 2011

Frequent coauthors

• Channing J. Der

  University of North Carolina at Chapel Hill

  79 shared

• Nikolay V. Dokholyan

  Hershey (United States)

  31 shared

• Stephen G. Chaney

  University of North Carolina at Chapel Hill

  28 shared

• Jonelle K. Drugan

  National Institutes of Health

  28 shared

• Peter J. Domaille

  University of Montana

  27 shared

• Kent L. Rossman

  25 shared

• Adrienne D. Cox

  University of North Carolina at Chapel Hill

  23 shared

• Jongyun Heo

  The University of Texas at Arlington

  22 shared

Labs

• CAMPBELL LABPI

Education

• PhD, Chemistry

  Yale University

Awards & honors

• OGE Mentoring Award - 2023
• Liebscher Distinguished Professorship
• Battle Distinguished Cancer Research Award