Protein kinase A-dependent phosphorylation of Dock180 at serine residue 1250 is important for glioma growth and invasion stimulated by platelet derived-growth factor receptor α

被引：17

作者：

Feng, Haizhong ^{[1
,2
]}

Li, Yanxin ^{[3
]}

Yin, Yuhua ^{[4
]}

Zhang, Weiwei ^{[1
]}

Hou, Yanli ^{[1
,5
]}

Zhang, Lei ^{[1
]}

Li, Zuoqing ^{[1
]}

Xie, Baoshu ^{[4
]}

Gao, Wei-Qiang ^{[1
]}

Sarkaria, Jann N. ^{[6
]}

Raizer, Jeffery J. ^{[2
]}

James, C. David ^{[7
]}

Parsa, Andrew T. ^{[7
]}

Hu, Bo ^{[2
]}

Cheng, Shi-Yuan ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Renji Med Clin Stem Cell Res Ctr X, Ren Ji Hosp,Sch Med, Shanghai 200030, Peoples R China

[2] Northwestern Univ, Feinberg Sch Med, Dept Neurol,Robert H Lurie Comprehens Canc Ctr, Northwestern Brain Tumor Inst,Ctr Genet Med, Chicago, IL 60611 USA

[3] Shanghai Jiao Tong Univ, Key Lab Pediat Hematol & Oncol, Minist Hlth,Pediat Translat Med Inst, Shanghai Childrens Med Ctr,Sch Med, Shanghai 200030, Peoples R China

[4] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Dept Neurol Surg, Shanghai 200030, Peoples R China

[5] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Dept Radiotherapy, Shanghai 200030, Peoples R China

[6] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA

[7] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Dept Neurol Surg,Northwestern Brain Tumor Inst, Chicago, IL 60611 USA

来源：

NEURO-ONCOLOGY | 2015年 / 17卷 / 06期

基金：

中国国家自然科学基金;

关键词：

Dock180; glioblastomas; PDGFR alpha; phosphorylation; PKA; NEWLY-DIAGNOSED GLIOBLASTOMA; NUCLEOTIDE-EXCHANGE FACTORS; TYROSINE KINASES; ACTIVATION; CELLS; DYNAMICS; TUMORIGENESIS; HETEROGENEITY; AMPLIFICATION; BEVACIZUMAB;

D O I：

10.1093/neuonc/nou323

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background. Dedicator of cytokinesis 1 (Dock1 or Dock180), a bipartite guanine nucleotide exchange factor for Rac1, plays critical roles in receptor tyrosine kinase-stimulated cancer growth and invasion. Dock180 activity is required in cell migration cancer tumorigenesis promoted by platelet derived growth factor receptor (PDGFR) and epidermal growth factor receptor. Methods. To demonstrate whether PDGFR alpha promotes tumor malignant behavior through protein kinase A (PKA)-dependent serine phosphorylation of Dock180, we performed cell proliferation, viability, migration, immunoprecipitation, immunoblotting, colony formation, and in vivo tumorigenesis assays using established and short-term explant cultures of glioblastoma cell lines. Results. Stimulation of PDGFR alpha results in phosphorylation of Dock180 at serine residue 1250 (S1250), whereas PKA inhibitors H-89 and KT5720 oppose this phosphorylation. S1250 locates within the Rac1-binding Dock homology region 2 domain of Dock180, and its phosphorylation activates Rac1, p-Akt, and phosphorylated extracellular signal-regulated kinase 1/2, while promoting cell migration, in vitro. By expressing RNA interference (RNAi)-resistant wild-type Dock180, but not mutant Dock180 S1250L, we were able to rescue PDGFR alpha-associated signaling and biological activities in cultured glioblastoma multiforme (GBM) cells that had been treated with RNAi for suppression of endogenous Dock180. In addition, expression of the same RNAi-resistant Dock180 rescued an invasive phenotype of GBM cells following intracranial engraftment in immunocompromised mice. Conclusion. These data describe an important mechanism by which PDGFR alpha promotes glioma malignant phenotypes through PKA-dependent serine phosphorylation of Dock180, and the data thereby support targeting the PDGFR alpha-PKA-Dock180-Rac1 axis for treating GBM with molecular profiles indicating PDGFR alpha signaling dependency.

引用

页码：832 / 842

页数：11

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