Matthew Waitkus

Positions:

Assistant Professor in Neurosurgery

Neurosurgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.S. 2009

The Ohio State University College of Medicine

Ph.D. 2014

Cleveland State University

Grants:

Role of GLUD2 as a metabolic driver of gliomas with IDH1 mutations

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Synthetic lethal strategies for targeting ATRX deficiency and the Alternative Lengthening of Telomeres in Pediatric High-Grade Gliomas

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
Uncle Kory Foundation
Role
Principal Investigator
Start Date
End Date

Publications:

Signal integration and gene induction by a functionally distinct STAT3 phosphoform.

Aberrant activation of the ubiquitous transcription factor STAT3 is a major driver of solid tumor progression and pathological angiogenesis. STAT3 activity is regulated by numerous posttranslational modifications (PTMs), including Tyr(705) phosphorylation, which is widely used as an indicator of canonical STAT3 function. Here, we report a noncanonical mechanism of STAT3 activation that occurs independently of Tyr(705) phosphorylation. Using quantitative liquid chromatography-tandem mass spectrometry, we have discovered and characterized a novel STAT3 phosphoform that is simultaneously phosphorylated at Thr(714) and Ser(727) by glycogen synthase kinase 3α and -β (GSK-3α/β). Both Thr(714) and Ser(727) are required for STAT3-dependent gene induction in response to simultaneous activation of epidermal growth factor receptor (EGFR) and protease-activated receptor 1 (PAR-1) in endothelial cells. In this combinatorial signaling context, preventing formation of doubly phosphorylated STAT3 by depleting GSK-3α/β is sufficient to disrupt signal integration and inhibit STAT3-dependent gene expression. Levels of doubly phosphorylated STAT3 but not of Tyr(705)-phosphorylated STAT3 are remarkably elevated in clear-cell renal-cell carcinoma relative to adjacent normal tissue, suggesting that the GSK-3α/β-STAT3 pathway is active in the disease. Collectively, our results describe a functionally distinct, noncanonical STAT3 phosphoform that positively regulates target gene expression in a combinatorial signaling context and identify GSK-3α/β-STAT3 signaling as a potential therapeutic target in renal-cell carcinoma.
Authors
Waitkus, MS; Chandrasekharan, UM; Willard, B; Tee, TL; Hsieh, JK; Przybycin, CG; Rini, BI; Dicorleto, PE
MLA Citation
Waitkus, Matthew S., et al. “Signal integration and gene induction by a functionally distinct STAT3 phosphoform.Mol Cell Biol, vol. 34, no. 10, May 2014, pp. 1800–11. Pubmed, doi:10.1128/MCB.00034-14.
URI
https://scholars.duke.edu/individual/pub1162610
PMID
24615012
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
34
Published Date
Start Page
1800
End Page
1811
DOI
10.1128/MCB.00034-14

Release of nonmuscle myosin II from the cytosolic domain of tumor necrosis factor receptor 2 is required for target gene expression.

Tumor necrosis factor-α (TNF-α) elicits its biological activities through activation of TNF receptor 1 (TNFR1, also known as p55) and TNFR2 (also known as p75). The activities of both receptors are required for the TNF-α-induced proinflammatory response. The adaptor protein TNFR-associated factor 2 (TRAF2) is critical for either p55- or p75-mediated activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, as well as for target gene expression. We identified nonmuscle myosin II (myosin) as a binding partner of p75. TNF-α-dependent signaling by p75 and induction of target gene expression persisted substantially longer in cells deficient in myosin regulatory light chain (MRLC; a component of myosin) than in cells replete in myosin. In resting endothelial cells, myosin was bound constitutively to the intracellular region of p75, a region that overlaps with the TRAF2-binding domain, and TNF-α caused the rapid dissociation of myosin from p75. At early time points after exposure to TNF-α, p75 activated Rho-associated kinase 1 (ROCK1). Inhibition of ROCK1 activity blocked TNF-α-dependent phosphorylation of MRLC and the dissociation of myosin from p75. ROCK1-dependent release of myosin was necessary for the TNF-α-dependent recruitment of TRAF2 to p75 and for p75-specific activation of NF-κB and MAPK signaling. Thus, our findings have revealed a previously uncharacterized, noncanonical regulatory function of myosin in cytokine signaling.
Authors
Chandrasekharan, UM; Dechert, L; Davidson, UI; Waitkus, M; Mavrakis, L; Lyons, K; Beach, JR; Li, X; Egelhoff, TT; Fox, PL; DiCorleto, PE
MLA Citation
Chandrasekharan, Unni M., et al. “Release of nonmuscle myosin II from the cytosolic domain of tumor necrosis factor receptor 2 is required for target gene expression.Sci Signal, vol. 6, no. 284, July 2013, p. ra60. Pubmed, doi:10.1126/scisignal.2003743.
URI
https://scholars.duke.edu/individual/pub1162611
PMID
23861542
Source
pubmed
Published In
Sci Signal
Volume
6
Published Date
Start Page
ra60
DOI
10.1126/scisignal.2003743

Targeting Isocitrate Dehydrogenase Mutations in Cancer: Emerging Evidence and Diverging Strategies.

Isocitrate dehydrogenase (IDH) active-site mutations cause a neomorphic enzyme activity that results in the formation of supraphysiologic concentrations of D-2-hydroxyglutarate (D-2HG). D-2HG is thought to be an oncometabolite that drives the formation of cancers in a variety of tissue types by altering the epigenetic state of progenitor cells by inhibiting enzymes involved in histone and DNA demethylation. This model has led to the development of pharmacologic inhibitors of mutant IDH activity for anticancer therapy, which are now being tested in several clinical trials. Emerging evidence in preclinical glioma models suggests that the epigenetic changes induced by D-2HG may persist even after mutant IDH activity is inhibited and D-2HG has returned to basal levels. Therefore, these results have raised questions as to whether the exploitation of downstream synthetic lethal vulnerabilities, rather than direct inhibition of mutant IDH1, will prove to be a superior therapeutic strategy. In this review, we summarize the preclinical evidence in gliomas and other models on the induction and persistence of D-2HG-induced hypermethylation of DNA and histones, and we examine emerging lines of evidence related to altered DNA repair mechanisms in mutant IDH tumors and their potential for therapeutic exploitation.
Authors
MLA Citation
Waitkus, Matthew S., and Hai Yan. “Targeting Isocitrate Dehydrogenase Mutations in Cancer: Emerging Evidence and Diverging Strategies.Clin Cancer Res, vol. 27, no. 2, Jan. 2021, pp. 383–88. Pubmed, doi:10.1158/1078-0432.CCR-20-1827.
URI
https://scholars.duke.edu/individual/pub1459997
PMID
32883741
Source
pubmed
Published In
Clinical Cancer Research
Volume
27
Published Date
Start Page
383
End Page
388
DOI
10.1158/1078-0432.CCR-20-1827

STAT3-mediated coincidence detection regulates noncanonical immediate early gene induction.

Signaling pathways interact with one another to form dynamic networks in which the cellular response to one stimulus may depend on the presence, intensity, timing, or localization of other signals. In rare cases, two stimuli may be simultaneously required for cells to elicit a significant biological output. This phenomenon, generally termed "coincidence detection," requires a downstream signaling node that functions as a Boolean AND gate to restrict biological output from a network unless multiple stimuli are received within a specific window of time. Simultaneous activation of the EGF receptor (EGFR) and a thrombin receptor (protease-activated receptor-1, PAR-1) increases the expression of multiple immediate early genes (IEGs) associated with growth and angiogenesis. Using a bioinformatic comparison of IEG promoter regions, we identified STAT3 as a critical transcription factor for the detection of coincident EGFR/PAR-1 activation. EGFR activation induces classical STAT3 Tyr(705) phosphorylation but also initiates an inhibitory signal through the PI3K-AKT signaling axis that prevents STAT3 Ser(727) phosphorylation. Coincident PAR-1 signaling resolves these conflicting EGF-activated pathways by blocking AKT activation and permitting GSK-3α/β-dependent STAT3 Ser(727) phosphorylation and STAT3-dependent gene expression. Functionally, combinatorial EGFR/PAR-1 signaling suppresses EGF-induced proliferation and thrombin-induced leukocyte adhesion and triggers a STAT3-dependent increase in endothelial cell migration. This study reveals a novel signaling role for STAT3 in which the simultaneous presence of extracellular EGF and thrombin is detected at the level of STAT3 post-translational modifications. Collectively, our results describe a novel regulatory mechanism in which combinatorial EGFR/PAR-1 signaling regulates STAT3-dependent IEG induction and endothelial cell migration.
Authors
Waitkus, MS; Chandrasekharan, UM; Willard, B; Haque, SJ; DiCorleto, PE
MLA Citation
Waitkus, Matthew S., et al. “STAT3-mediated coincidence detection regulates noncanonical immediate early gene induction.J Biol Chem, vol. 288, no. 17, Apr. 2013, pp. 11988–2003. Pubmed, doi:10.1074/jbc.M112.428516.
URI
https://scholars.duke.edu/individual/pub1162612
PMID
23504318
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
288
Published Date
Start Page
11988
End Page
12003
DOI
10.1074/jbc.M112.428516

Synergistic induction of mitogen-activated protein kinase phosphatase-1 by thrombin and epidermal growth factor requires vascular endothelial growth factor receptor-2.

OBJECTIVE: To determine the molecular mechanism underlying the synergistic response of mitogen-activated protein kinase phosphatase-1 (MKP-1), which is induced by thrombin and epidermal growth factor (EGF). METHODS AND RESULTS: MKP-1 induction by thrombin (approximately 6-fold) was synergistically increased (approximately 18-fold) by cotreatment with EGF in cultured endothelial cells. EGF alone did not induce MKP-1 substantially (<2-fold). The synergistic induction of MKP-1 was not mediated by matrix metalloproteinases. The EGF receptor kinase inhibitor AG1478 blocked approximately 70% of MKP-1 induction by thrombin plus EGF (from 18- to 6-fold) but not the response to thrombin alone. An extracellular signal-regulated kinase (ERK)-dependent protease-activated receptor-1 (PAR-1) signal was required for the thrombin alone effect; an ERK-independent PAR-1 signal was necessary for the approximately 12-fold MKP-1 induction by thrombin plus EGF. VEGF induction of MKP-1 was also approximately 12-fold and c-Jun N-terminal kinase (JNK) dependent. Inhibitors of extracellular signal-regulated kinase and JNK activation blocked thrombin plus EGF-induced MKP-1 completely. Furthermore, VEGF receptor 2 depletion blocked the synergistic response without affecting the induction of MKP-1 by thrombin alone. CONCLUSIONS: We have identified a novel signaling interaction between protease-activated receptor-1 and EGF receptor that is mediated by VEGF receptor 2 and results in synergistic MKP-1 induction.
Authors
Chandrasekharan, UM; Waitkus, M; Kinney, CM; Walters-Stewart, A; DiCorleto, PE
MLA Citation
Chandrasekharan, Unni M., et al. “Synergistic induction of mitogen-activated protein kinase phosphatase-1 by thrombin and epidermal growth factor requires vascular endothelial growth factor receptor-2.Arterioscler Thromb Vasc Biol, vol. 30, no. 10, Oct. 2010, pp. 1983–89. Pubmed, doi:10.1161/ATVBAHA.110.212399.
URI
https://scholars.duke.edu/individual/pub1162613
PMID
20671228
Source
pubmed
Published In
Arterioscler Thromb Vasc Biol
Volume
30
Published Date
Start Page
1983
End Page
1989
DOI
10.1161/ATVBAHA.110.212399