Structural Basis of Membrane Targeting by the Dock180 Family of Rho Family Guanine Exchange Factors (Rho-GEFs)

Premkumar, Lakshmanane; Bobkov, Andrey A.; Patel, Manishha; Jaroszewski, Lukasz; Bankston, Laurie A.; Stec, Boguslaw; Vuori, Kristiina; Côté, Jean‐François; Liddington, Robert

doi:10.1074/jbc.m110.102517

Cited by 63 publications

(71 citation statements)

References 87 publications

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“…Interaction of Dock180 with PDGFRα could additionally target Dock180 to the membrane in synergy with the DHR-1 domain, inducing formation of the Dock180/CrkII/p130 Cas complex and stimulating Rac1 activities and cell motility (11). These data also support the hypothesis that DHR-1 plays a role in dynamic membrane targeting of the Rho GEF activity of Dock180 in PDGFRα-activated cells (33). On the other hand, we found that association of Dock180 to PDGFRα was independent of Src-induced p-Dock180 Y1811 , since the Dock180 Y1811F mutant was still able to bind to PDGFRα upon PDGF-A stimulation.…”

Section: Discussionsupporting

confidence: 77%

Activation of Rac1 by Src-dependent phosphorylation of Dock180Y1811 mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans

Feng¹,

Hu²,

Liu³

et al. 2011

J. Clin. Invest.

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105

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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.

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Section: Discussionsupporting

confidence: 77%

Activation of Rac1 by Src-dependent phosphorylation of Dock180Y1811 mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans

Feng¹,

Hu²,

Liu³

et al. 2011

J. Clin. Invest.

Self Cite

105

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“…1 and 2B). Helices ␣4 and ␣5 of lobe A generate the homodimeric interface, previously observed in DOCK9 DHR2 , confirming the prediction that all DOCK DHR2 domains self-associate through a conserved dimerization mechanism (31) and in agreement with findings that the closely related DOCK A subfamily member DOCK1 is an oligomer (19,42).…”

Section: Dhr2supporting

confidence: 76%

Multiple Factors Confer Specific Cdc42 and Rac Protein Activation by Dedicator of Cytokinesis (DOCK) Nucleotide Exchange Factors

Kulkarni

Yang

Zhang

et al. 2011

Journal of Biological Chemistry

116

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To understand the molecular basis for DOCK-GTPase specificity, we have determined the crystal structure of DOCK2 DHR2 in complex with Rac1. DOCK2 DHR2 and DOCK9 DHR2 exhibit similar tertiary structures and homodimer interfaces and share a conserved GTPase-activating mechanism. Multiple structural differences between DOCK2 DHR2 and DOCK9 DHR2 account for their selectivity toward Rac1 and Cdc42. Key determinants of selectivity of Cdc42 and Rac for their cognate DOCK DHR2 are a Phe or Trp residue within ␤3 (residue 56) and the ability of DOCK proteins to exploit differences in the GEF-induced conformational changes of switch 1 dependent on a divergent residue at position 27. DOCK proteins, therefore, differ from DH-PH GEFs that select their cognate GTPases through recognition of structural differences within the ␤2/␤3 strands.

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“…83 In addition to this exception, some GEFs (e.g., ARNO/DOCK family) completely lack a PH domain and use a BAR domain to interact with curved membrane. 84 Nonetheless, PH domains in many GEFs are responsible for their subcellular localization and are required for proper GTPase activation. Binding of the PH domain to phospholipids orientates the associated DH domain correctly for proper GTPase activation.…”

Section: Gefs and Gapsmentioning

confidence: 99%

Leukocyte transendothelial migration: A local affair

2016

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Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens. It serves as a protective response that involves leukocytes, blood vessels and molecular mediators with the purpose to eliminate the initial cause of cell injury and to initiate tissue repair. Inflammation is tightly regulated by the body and is associated with transient crossing of leukocytes through the blood vessel wall, a process called transendothelial migration (TEM) or diapedesis. TEM is a close collaboration between leukocytes on one hand and the endothelium on the other. Limiting vascular leakage during TEM but also when the leukocyte has crossed the endothelium is essential for maintaining vascular homeostasis. Although many details have been uncovered during the recent years, the molecular mechanisms from the vascular part that drive TEM still shows significant gaps in our understanding. This review will focus on the local signals that are induced in the endothelium that regulate leukocyte TEM and simultaneous preservation of endothelial barrier function.

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Structural Basis of Membrane Targeting by the Dock180 Family of Rho Family Guanine Exchange Factors (Rho-GEFs)

Cited by 63 publications

References 87 publications

Activation of Rac1 by Src-dependent phosphorylation of Dock180Y1811 mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans

Activation of Rac1 by Src-dependent phosphorylation of Dock180Y1811 mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans

Multiple Factors Confer Specific Cdc42 and Rac Protein Activation by Dedicator of Cytokinesis (DOCK) Nucleotide Exchange Factors

Leukocyte transendothelial migration: A local affair

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