Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma

Teresa Purzner, James Purzner, Taylor Buckstaff, Giorgio Cozza, Sharareh Gholamin, Jessica M. Rusert, Tom A. Hartl, John Sanders, Nicholas Conley, Xuecai Ge, Marc Langan, Vijay Ramaswamy, Lauren Ellis, Ulrike Litzenburger, Sara Bolin, Johanna Theruvath, Ryan Nitta, Lin Qi, Xiao Nan Li, Gordon Li & 7 others Michael D. Taylor, Robert J. Wechsler-Reya, Lorenzo A. Pinna, Yoon-Jae Cho, Margaret T. Fuller, Joshua E. Elias, Matthew P. Scott

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology.

Original languageEnglish (US)
Article numbereaau5147
JournalScience Signaling
Volume11
Issue number547
DOIs
StatePublished - Sep 11 2018

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Medulloblastoma
Hedgehogs
Phosphotransferases
Tumors
Phosphorylation
Pharmaceutical Preparations
Neurons
Bearings (structural)
Therapeutics
Casein Kinase II
Pediatrics
Pathology
Neoplasms
Brain
Developmental Biology
Transcription Factors
Stabilization
Cells
Growth
Drug Resistance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Purzner, T., Purzner, J., Buckstaff, T., Cozza, G., Gholamin, S., Rusert, J. M., ... Scott, M. P. (2018). Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma. Science Signaling, 11(547), [eaau5147]. https://doi.org/10.1126/scisignal.aau5147

Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma. / Purzner, Teresa; Purzner, James; Buckstaff, Taylor; Cozza, Giorgio; Gholamin, Sharareh; Rusert, Jessica M.; Hartl, Tom A.; Sanders, John; Conley, Nicholas; Ge, Xuecai; Langan, Marc; Ramaswamy, Vijay; Ellis, Lauren; Litzenburger, Ulrike; Bolin, Sara; Theruvath, Johanna; Nitta, Ryan; Qi, Lin; Li, Xiao Nan; Li, Gordon; Taylor, Michael D.; Wechsler-Reya, Robert J.; Pinna, Lorenzo A.; Cho, Yoon-Jae; Fuller, Margaret T.; Elias, Joshua E.; Scott, Matthew P.

In: Science Signaling, Vol. 11, No. 547, eaau5147, 11.09.2018.

Research output: Contribution to journalArticle

Purzner, T, Purzner, J, Buckstaff, T, Cozza, G, Gholamin, S, Rusert, JM, Hartl, TA, Sanders, J, Conley, N, Ge, X, Langan, M, Ramaswamy, V, Ellis, L, Litzenburger, U, Bolin, S, Theruvath, J, Nitta, R, Qi, L, Li, XN, Li, G, Taylor, MD, Wechsler-Reya, RJ, Pinna, LA, Cho, Y-J, Fuller, MT, Elias, JE & Scott, MP 2018, 'Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma', Science Signaling, vol. 11, no. 547, eaau5147. https://doi.org/10.1126/scisignal.aau5147
Purzner, Teresa ; Purzner, James ; Buckstaff, Taylor ; Cozza, Giorgio ; Gholamin, Sharareh ; Rusert, Jessica M. ; Hartl, Tom A. ; Sanders, John ; Conley, Nicholas ; Ge, Xuecai ; Langan, Marc ; Ramaswamy, Vijay ; Ellis, Lauren ; Litzenburger, Ulrike ; Bolin, Sara ; Theruvath, Johanna ; Nitta, Ryan ; Qi, Lin ; Li, Xiao Nan ; Li, Gordon ; Taylor, Michael D. ; Wechsler-Reya, Robert J. ; Pinna, Lorenzo A. ; Cho, Yoon-Jae ; Fuller, Margaret T. ; Elias, Joshua E. ; Scott, Matthew P. / Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma. In: Science Signaling. 2018 ; Vol. 11, No. 547.
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AU - Li, Xiao Nan

AU - Li, Gordon

AU - Taylor, Michael D.

AU - Wechsler-Reya, Robert J.

AU - Pinna, Lorenzo A.

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