Ronald L Hamilton

Publications (3)40.45 Total impact

• Source

  Available from: Shi-Yuan Cheng

  Article: Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis.

  Haizhong Feng, Bo Hu, Michael J Jarzynka, Yanxin Li, Susan Keezer, Terrance G Johns, Careen K Tang, Ronald L Hamilton, Kristiina Vuori, Ryo Nishikawa, Jann N Sarkaria, Tim Fenton, Tao Cheng, Frank B Furnari, Webster K Cavenee, Shi-Yuan Cheng
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  ABSTRACT: Glioblastoma, the most common primary malignant cancer of the brain, is characterized by rapid tumor growth and infiltration of tumor cells throughout the brain. These traits cause glioblastomas to be highly resistant to current therapies with a resultant poor prognosis. Although aberrant oncogenic signaling driven by signature genetic alterations, such as EGF receptor (EGFR) gene amplification and mutation, plays a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here, we report that EGFRvIII (also known as ΔEGFR and de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in human glioblastoma, promotes tumorigenesis through Src family kinase (SFK)-dependent phosphorylation of Dock180, a guanine nucleotide exchange factor for Rac1. EGFRvIII induces phosphorylation of Dock180 at tyrosine residue 722 (Dock180(Y722)) and stimulates Rac1-signaling, glioblastoma cell survival and migration. Consistent with this being causal, siRNA knockdown of Dock180 or expression of a Dock180(Y722F) mutant inhibits each of these EGFRvIII-stimulated activities. The SFKs, Src, Fyn, and Lyn, induce phosphorylation of Dock180(Y722) and inhibition of these SFKs by pharmacological inhibitors or shRNA depletion markedly attenuates EGFRvIII-induced phosphorylation of Dock180(Y722), Rac1 activity, and glioblastoma cell migration. Finally, phosphorylated Dock180(Y722) is coexpressed with EGFRvIII and phosphorylated Src(Y418) in clinical specimens, and such coexpression correlates with an extremely poor survival in glioblastoma patients. These results suggest that targeting the SFK-p-Dock180(Y722)-Rac1 signaling pathway may offer a novel therapeutic strategy for glioblastomas with EGFRvIII overexpression.
  Proceedings of the National Academy of Sciences 02/2012; 109(8):3018-23. · 9.68 Impact Factor
• Article: Activation of Rac1 by Src-dependent phosphorylation of Dock180(Y1811) mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans.

  Haizhong Feng, Bo Hu, Kun-Wei Liu, Yanxin Li, Xinghua Lu, Tao Cheng, Jia-Jean Yiin, Songjian Lu, Susan Keezer, Tim Fenton, Frank B Furnari, Ronald L Hamilton, Kristiina Vuori, Jann N Sarkaria, Motoo Nagane, Ryo Nishikawa, Webster K Cavenee, Shi-Yuan Cheng
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  ABSTRACT: Two hallmarks of glioblastoma multiforme, the most common malignant brain cancer in humans, are aggressive growth and the ability of single glioma cells to disperse throughout the brain. These characteristics render tumors resistant to current therapies and account for the poor prognosis of patients. Although it is known that oncogenic signaling caused by overexpression of genes such as PDGFRA is responsible for robust glioma growth and cell infiltration, the mechanisms underlying glioblastoma malignancy remain largely elusive. Here, we report that PDGFRα signaling in glioblastomas leads to Src-dependent phosphorylation of the guanine nucleotide exchange factor Dock180 at tyrosine 1811 (Dock180(Y1811)) that results in activation of the GTPase Rac1 and subsequent cell growth and invasion. In human glioma cells, knockdown of Dock180 and reversion with an RNAi-resistant Dock180(Y1811F) abrogated, whereas an RNAi-resistant Dock180(WT) rescued, PDGFRα-promoted glioma growth, survival, and invasion. Phosphorylation of Dock180(Y1811) enhanced its association with CrkII and p130(Cas), causing activation of Rac1 and consequent cell motility. Dock180 also associated with PDGFRα to promote cell migration. Finally, phosphorylated Dock180(Y1811) was detected in clinical samples of gliomas and various types of human cancers, and coexpression of phosphorylated Dock180(Y1811), phosphorylated Src(Y418), and PDGFRα was predictive of extremely poor prognosis of patients with gliomas. Taken together, our findings provide insight into PDGFRα-stimulated gliomagenesis and suggest that phosphorylated Dock180(Y1811) contributes to activation of Rac1 in human cancers with PDGFRA amplification.
  The Journal of clinical investigation 11/2011; 121(12):4670-84. · 15.39 Impact Factor
• Article: SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans.

  Kun-Wei Liu, Haizhong Feng, Robert Bachoo, Andrius Kazlauskas, Erin M Smith, Karen Symes, Ronald L Hamilton, Motoo Nagane, Ryo Nishikawa, Bo Hu, Shi-Yuan Cheng
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  ABSTRACT: Recent collaborative efforts have subclassified malignant glioblastomas into 4 clinical relevant subtypes based on their signature genetic lesions. Platelet-derived growth factor receptor α (PDGFRA) overexpression is concomitant with a loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype of glioblastomas. Here we report that activation of PDGFRα conferred tumorigenicity to Ink4a/Arf-deficient mouse astrocytes and human glioma cells in the brain. Restoration of p16INK4a but not p19ARF suppressed PDGFRα-promoted glioma formation. Mechanistically, abrogation of signaling modules in PDGFRα that lost capacity to bind to SHP-2 or PI3K significantly diminished PDGFRα-promoted tumorigenesis. Furthermore, inhibition of SHP-2 by shRNAs or pharmacological inhibitors disrupted the interaction of PI3K with PDGFRα, suppressed downstream AKT/mTOR activation, and impaired tumorigenesis of Ink4a/Arf-null cells, whereas expression of an activated PI3K mutant rescued the effect of SHP-2 inhibition on tumorigenicity. PDGFRα and PDGF-A are coexpressed in clinical glioblastoma specimens, and such co-expression is linked with activation of SHP-2/AKT/mTOR signaling. Together, our data suggest that in glioblastomas with Ink4a/Arf deficiency, overexpressed PDGFRα promotes tumorigenesis through the PI3K/AKT/mTOR-mediated pathway regulated by SHP-2 activity. These findings functionally validate the genomic analysis of glioblastomas and identify SHP-2 as a potential target for treatment of glioblastomas.
  The Journal of clinical investigation 02/2011; 121(3):905-17. · 15.39 Impact Factor