Understanding the Mechanism of Protein Kinases Drak/STK17A and RIOK2 function in Glioblastoma Pubblico

Abstract

Glioblastoma (GBM) is the most common adult primary malignant brain tumors and is resistant to current therapies. Genomic analyses reveal that signature genetic lesions in GBM include copy gain and amplification of chromosome 7, amplification, mutation, and/or overexpression of receptor tyrosine kinases (RTKs), such as EGFR, and activating mutations in components of the PI-3 kinase (PI3K) pathway. In Drosophila melanogaster, constitutive co- activation of RTK and PI3K signaling in glial progenitor cells recapitulate key features of human gliomas. Using our Drosophila glioma model to elucidate new downstream effectors of EGFR and PI3K signaling pathways, we discovered two novel protein kinases involved in GBM tumorigenesis through two disparate mechanisms: Death-associated protein kinase (Drak), a cytoplasmic serine/threonine kinase orthologous to the human kinase STK17A, and right open reading frame kinase 2 (RIOK2), an atypical serine/threonine kinase.

We discovered that Drak is necessary for glial neoplasia, but not for normal glial proliferation and development and cooperates with EGFR to promote glial cell transformation. Furthermore, our results indicate that Drak phosphorylates Sqh, the Drosophila ortholog of MRLC (non-muscle myosin regulatory light chain), and recruits Anillin, a binding partner of phosphorylated Sqh, to drive glial cell transformation. The Drak-Sqh-Anillin complex co- localizes in neoplastic cells undergoing mitosis and cytokinesis. These functional relationships were conserved in human GBM. Our results indicate that Drak/STK17A, the substrate Sqh/MRLC, and the effector Anillin/ANLN regulate mitosis and cytokinesis in gliomas.

We also discovered that dRIOK2 forms a complex with RNA-binding protein, Imp, the Drosophila ortholog of IGF2BP3 (IMP3), and that both dRIOK2 and Imp are necessary for glial neoplasia, but not for normal glial proliferation and development. Furthermore, our results indicate that RIOK2 catalytic activity is important for glial neoplasia and recruits TORC2 to phosphorylate IMP3, and in turn, regulate levels of MYC protein, a known target mRNA of IMP3. These functional relationships were conserved in human GBM. Collectively, our data indicates that RIOK2 autophosphorylation recruits TORC2 and IMP3, which in turn, modulates MYC protein expression to promote GBM tumorigenesis. The novel Drak/STK17A-Sqh/MRLC- Anillin/ANLN and RIOK-IMP3-TORC2 complexes may provide new therapeutic targets for gliomas. 

Table of Contents

Chapter 1. Introduction

1.1 Glioblastoma

1.2 Drosophila melanogaster: an effective tool to model GBM

1.3 Drosophila models for RTK-driven GBM

1.4 Drosophila models identify mechanosensory mechanisms in GBM

1.5 Drosophila models identify metabolic mechanisms in GBM tumorigenesis

1.6 Drosophila models and glioma stem cells

1.7 Tumor stem cells: a model for investigating essential biological pathways of GBM

1.8 STK17A: a novel protein kinase

1.9 RIOK2: a novel protein kinase

1.10 IMP3: a potential downstream effector of RIOK2

1.11 MYC and mTOR in Cancer

1.12. Dissertation Goals

Chapter 2. Drak/STK17A drives neoplastic glial proliferation through modulation of MRLC signaling

2.1 Abstract

2.2 Introduction

2.3 Materials and Methods

2.4 Results

2.5 Discussion

2.6 Supplementary Material

Chapter 3. RIOK2-IMP3-TORC2 complex drives neoplastic glial proliferation through modulation of MYC

3.1 Abstract

3.2 Introduction

3.3 Materials and Methods

3.4 Results

3.5 Discussion

3.6 Supplementary Material

Chapter 4. Discussion

4.1 Drak/STK17A in EGFR driven gliomagenesis

4.2 RIOK2 and IMP3 in gliomagenesis

4.3 Conclusions

References

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Cancer Biology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Cell Health Sciences, Oncology Biology, Neuroscience
Parola chiave	PI3K EGFR Signaling Transduction TORC2 Drak MYC STK17A Drosophila RIOK2 LGG Glioblastoma IGF2BP3
Committee Chair / Thesis Advisor	Renee D. Read, Emory University
Committee Members	Anita Corbett, Emory University Anna Kenney, Emory University Ken Moberg, Emory University Brian Petrich, Emory University Dolores Hambardzumyan, Mount Sinai Hospital

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