scholarly journals Uveal melanoma cells use ameboid and mesenchymal mechanisms of cell motility crossing the endothelium

2021 ◽  
pp. mbc.E20-04-0241
Author(s):  
Michael D. Onken ◽  
Kendall J. Blumer ◽  
John A. Cooper
Keyword(s):  
Immune Cells ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Direct Mechanism ◽  
Guanine Nucleotide Exchange ◽  
Amoeboid Motility ◽  
Nucleotide Exchange Factor ◽  
Oncogenic Mutations ◽  
The One ◽  
Pharmacologic Inhibition

Uveal melanomas (UM) are malignant cancers arising from the pigmented layers of the eye. UM cells spread through the bloodstream, and circulating UM cells are detectable in patients before metastases appear. Extravasation of UM cells is necessary for formation of metastases, and transendothelial migration (TEM) is a key step in extravasation. UM cells execute TEM via a stepwise process involving the actin-based processes of ameboid blebbing and mesenchymal lamellipodial protrusion. UM cancers are driven by oncogenic mutations that activate Gαq/11, and this activates TRIO, a guanine nucleotide exchange factor (GEF) for RhoA and Rac1. We found that pharmacologic inhibition of Gαq/11 in UM cells reduced TEM. Inhibition of the RhoA pathway blocked amoeboid motility but led to enhanced TEM; in contrast, inhibition of the Rac1 pathway decreased mesenchymal motility and reduced TEM. Inhibition of Arp2/3 complex allowed cells to transmigrate without intercalation, a direct mechanism similar to the one often displayed by immune cells. BAP1-deficient (+/-) UM subclones displayed motility behaviors and increased levels of TEM, similar to the effects of RhoA inhibitors. We conclude that RhoA and Rac1 signaling pathways, downstream of oncogenic Gαq/11, combine with pathways regulated by BAP1 to control the motility and transmigration of UM cells. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

scholarly journals Uveal melanoma cells use ameboid and mesenchymal mechanisms of cell motility crossing the endothelium

2020 ◽  
Author(s):  
Michael D. Onken ◽  
John A. Cooper
Keyword(s):  
Immune Cells ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Endothelial Monolayer ◽  
Direct Mechanism ◽  
Guanine Nucleotide Exchange ◽  
Amoeboid Motility ◽  
Nucleotide Exchange Factor ◽  
Oncogenic Mutations ◽  
Pharmacologic Inhibition

SUMMARYUveal melanomas (UM) are malignant cancers arising from the pigmented layers of the eye. UM cells spread through the bloodstream, and circulating UM cells are detectable in patients before metastases appear. Extravasation of UM cells, notably transendothelial migration (TEM), is a key step in formation of metastases. UM cells execute TEM via a stepwise process of intercalation into the endothelial monolayer involving the actin-based processes of ameboid blebbing and mesenchymal lamellipodial protrusion. UM cancers are driven by oncogenic mutations in Gαq/11, which activate TRIO, a guanine nucleotide exchange factor (GEF) for RhoA and Rac1. Pharmacologic inhibition of Gαq/11 in UM cells reduced TEM. Inhibition of the RhoA pathway blocked amoeboid motility but led to enhanced TEM; in contrast, inhibition of the Rac1 pathway decreased mesenchymal motility and reduced TEM. Inhibition of Arp2/3 also inhibited mesenchymal motility, but invasion was less affected; in this case, the amoeboid blebbing behavior of the cells led to transmigration without intercalation, a direct mechanism similar to that of immune cells. BAP1-deficient (+/−) UM subclones displayed motility behavior and increased levels of TEM, similar to effects of RhoA inhibitors. We conclude that RhoA and Rac1 signaling pathways, downstream of oncogenic Gαq/11, combine with pathways regulated by BAP1 to control the motility and transmigration of UM cells.

scholarly journals αPIX Rho GTPase Guanine Nucleotide Exchange Factor Regulates Lymphocyte Functions and Antigen Receptor Signaling

2008 ◽  
Vol 28 (11) ◽  
pp. 3776-3789 ◽  
Author(s):  
Karine Missy ◽  
Bin Hu ◽  
Kerstin Schilling ◽  
Anke Harenberg ◽  
Vadim Sakk ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Immune Cells ◽  
Rho Gtpase ◽  
Antigen Receptor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Antigen Receptor Signaling ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

ABSTRACT αPIX is a Rho GTPase guanine nucleotide exchange factor domain-containing signaling protein that associates with other proteins involved in cytoskeletal-membrane complexes. It has been shown that PIX proteins play roles in some immune cells, including neutrophils and T cells. In this study, we report the immune system phenotype of αPIX knockout mice. We extended αPIX expression experiments and found that whereas αPIX was specific to immune cells, its homolog βPIX was expressed in a wider range of cells. Mice lacking αPIX had reduced numbers of mature lymphocytes and defective immune responses. Antigen receptor-directed proliferation of αPIX− T and B cells was also reduced, but basal migration was enhanced. Accompanying these defects, formation of T-cell-B-cell conjugates and recruitment of PAK and Lfa-1 integrin to the immune synapse were impaired in the absence of αPIX. Proximal antigen receptor signaling was largely unaffected, with the exception of reduced phosphorylation of PAK and expression of GIT2 in both T cells and B cells. These results reveal specific roles for αPIX in the immune system and suggest that redundancy with βPIX precludes a more severe immune phenotype.

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