scholarly journals Rabgap1 promotes recycling of active β1 integrins to support effective cell migration

2020 ◽  
Vol 133 (18) ◽  
pp. jcs243683
Author(s):  
Anna V. Samarelli ◽  
Tilman Ziegler ◽  
Alexander Meves ◽  
Reinhard Fässler ◽  
Ralph T. Böttcher
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Adhesion Formation ◽  
Migration And Invasion ◽  
Β1 Integrin ◽  
Mouse Fibroblasts ◽  
Endosomal Recycling ◽  
Focal Adhesion Formation ◽  
Β1 Integrins ◽  
Npxy Motif

ABSTRACTIntegrin function depends on the continuous internalization of integrins and their subsequent endosomal recycling to the plasma membrane to drive adhesion dynamics, cell migration and invasion. Here we assign a pivotal role for Rabgap1 (GAPCenA) in the recycling of endocytosed active β1 integrins to the plasma membrane. The phosphotyrosine-binding (PTB) domain of Rabgap1 binds to the membrane-proximal NPxY motif in the cytoplasmic domain of β1 integrin subunits on endosomes. Silencing Rabgap1 in mouse fibroblasts leads to the intracellular accumulation of active β1 integrins, alters focal adhesion formation, and decreases cell migration and cancer cell invasion. Functionally, Rabgap1 facilitates active β1 integrin recycling to the plasma membrane through attenuation of Rab11 activity. Taken together, our results identify Rabgap1 as an important factor for conformation-specific integrin trafficking and define the role of Rabgap1 in β1-integrin-mediated cell migration in mouse fibroblasts and breast cancer cells.

scholarly journals Loss of ADAM9 expression impairs β1 integrin endocytosis, focal adhesion formation and cancer cell migration

2017 ◽  
Vol 131 (1) ◽  
pp. jcs205393 ◽  
Author(s):  
Kasper J. Mygind ◽  
Jeanette Schwarz ◽  
Pranshu Sahgal ◽  
Johanna Ivaska ◽  
Marie Kveiborg
Keyword(s):  
Cell Migration ◽  
Cancer Cell ◽  
Focal Adhesion ◽  
Adhesion Formation ◽  
Β1 Integrin ◽  
Cancer Cell Migration ◽  
Focal Adhesion Formation

scholarly journals Distinct roles of AKT isoforms in regulating β1-integrin activity, migration, and invasion in prostate cancer

2012 ◽  
Vol 23 (17) ◽  
pp. 3357-3369 ◽  
Author(s):  
Reetta Virtakoivu ◽  
Teijo Pellinen ◽  
Juha K. Rantala ◽  
Merja Perälä ◽  
Johanna Ivaska
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cell Migration ◽  
Tyrosine Kinases ◽  
Migration And Invasion ◽  
Β1 Integrin ◽  
Akt Isoforms ◽  
Feedback Suppression ◽  
Cancer Migration ◽  
Β1 Integrins

AKT1 and AKT2 kinases have been shown to play opposite roles in breast cancer migration and invasion. In this study, an RNA interference screen for integrin activity inhibitors identified AKT1 as an inhibitor of β1-integrin activity in prostate cancer. Validation experiments investigating all three AKT isoforms demonstrated that, unlike in breast cancer, both AKT1 and AKT2 function as negative regulators of cell migration and invasion in PC3 prostate cancer cells. Down-regulation of AKT1 and AKT2, but not AKT3, induced activation of cell surface β1-integrins and enhanced adhesion, migration, and invasion. Silencing of AKT1 and AKT2 also resulted in increased focal adhesion size. Importantly, the mechanisms involved in integrin activity regulation were distinct for the two AKT isoforms. Silencing of AKT1 relieved feedback suppression of the expression and activity of several receptor tyrosine kinases, including EGFR and MET, with established cross-talk with β1-integrins. Silencing of AKT2, on the other hand, induced up-regulation of the microRNA-200 (miR-200) family, and overexpression of miR-200 was sufficient to induce integrin activity and cell migration in PC3 cells. Taken together, these data define an inhibitory role for both AKT1 and AKT2 in prostate cancer migration and invasion and highlight the cell type–specific actions of AKT kinases in the regulation of cell motility.

scholarly journals CD81 regulates cell migration through its association with Rac GTPase

2013 ◽  
Vol 24 (3) ◽  
pp. 261-273 ◽  
Author(s):  
Emilio Tejera ◽  
Vera Rocha-Perugini ◽  
Soraya López-Martín ◽  
Daniel Pérez-Hernández ◽  
Alexia I. Bachir ◽  
...  
Keyword(s):  
Cell Migration ◽  
Adhesion Formation ◽  
Direct Interaction ◽  
Cytoplasmic Domain ◽  
Small Gtpase ◽  
Rac Gtpase ◽  
Soluble Peptide ◽  
Cross Correlation Analysis ◽  
Focal Adhesion Formation

CD81 is a member of the tetraspanin family that has been described to have a key role in cell migration of tumor and immune cells. To unravel the mechanisms of CD81-regulated cell migration, we performed proteomic analyses that revealed an interaction of the tetraspanin C-terminal domain with the small GTPase Rac. Direct interaction was confirmed biochemically. Moreover, microscopy cross-correlation analysis demonstrated the in situ integration of both molecules into the same molecular complex. Pull-down experiments revealed that CD81-Rac interaction was direct and independent of Rac activation status. Knockdown of CD81 resulted in enhanced protrusion rate, altered focal adhesion formation, and decreased cell migration, correlating with increased active Rac. Reexpression of wild-type CD81, but not its truncated form lacking the C-terminal cytoplasmic domain, rescued these effects. The phenotype of CD81 knockdown cells was mimicked by treatment with a soluble peptide with the C-terminal sequence of the tetraspanin. Our data show that the interaction of Rac with the C-terminal cytoplasmic domain of CD81 is a novel regulatory mechanism of the GTPase activity turnover. Furthermore, they provide a novel mechanism for tetraspanin-dependent regulation of cell motility and open new avenues for tetraspanin-targeted reagents by the use of cell-permeable peptides.

scholarly journals CD13 tethers the IQGAP1-ARF6-EFA6 complex to the plasma membrane to promote ARF6 activation, β1 integrin recycling, and cell migration

2019 ◽  
Vol 12 (579) ◽  
pp. eaav5938 ◽  
Author(s):  
Mallika Ghosh ◽  
Robin Lo ◽  
Ivan Ivic ◽  
Brian Aguilera ◽  
Veneta Qendro ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Attachment ◽  
Leading Edge ◽  
Small Gtpase ◽  
Β1 Integrin ◽  
Recycling Endosomes ◽  
Cellular Processes ◽  
Early Endosomes

Cell attachment to the extracellular matrix (ECM) requires a balance between integrin internalization and recycling to the surface that is mediated by numerous proteins, emphasizing the complexity of these processes. Upon ligand binding in various cells, the β1 integrin is internalized, traffics to early endosomes, and is returned to the plasma membrane through recycling endosomes. This trafficking process depends on the cyclical activation and inactivation of small guanosine triphosphatases (GTPases) by their specific guanine exchange factors (GEFs) and their GTPase-activating proteins (GAPs). In this study, we found that the cell surface antigen CD13, a multifunctional transmembrane molecule that regulates cell-cell adhesion and receptor-mediated endocytosis, also promoted cell migration and colocalized with β1 integrin at sites of cell adhesion and at the leading edge. A lack of CD13 resulted in aberrant trafficking of internalized β1 integrin to late endosomes and its ultimate degradation. Our data indicate that CD13 promoted ARF6 GTPase activity by positioning the ARF6-GEF EFA6 at the cell membrane. In migrating cells, a complex containing phosphorylated CD13, IQGAP1, GTP-bound (active) ARF6, and EFA6 at the leading edge promoted the ARF6 GTPase cycling and cell migration. Together, our findings uncover a role for CD13 in the fundamental cellular processes of receptor recycling, regulation of small GTPase activities, cell-ECM interactions, and cell migration.

VEGFR-1 (FLT-1), β1 integrin, and hERG K+ channel for a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1238-1250 ◽  
Author(s):  
Serena Pillozzi ◽  
Maria Felice Brizzi ◽  
Pietro Antonio Bernabei ◽  
Benedetta Bartolozzi ◽  
Roberto Caporale ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Migration ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Migration And Invasion ◽  
Β1 Integrin ◽  
Acute Leukemias ◽  
Signaling Complex ◽  
Macromolecular Signaling Complex ◽  
Acute Myeloid

Abstract Leukemia cell motility and transendothelial migration into extramedullary sites are regulated by angiogenic factors and are considered unfavorable prognostic factors in acute leukemias. We have studied cross talk among (1) the vascular endothelial growth factor receptor-1, FLT-1; (2) the human eag-related gene 1 (hERG1) K+ channels; and (3) integrin receptors in acute myeloid leukemia (AML) cells. FLT-1, hERG1, and the β1 integrin were found to form a macromolecular signaling complex. The latter mostly recruited the hERG1B isoform of hERG1 channels, and its assembly was necessary for FLT-1 signaling activation and AML cell migration. Both effects were inhibited when hERG1 channels were specifically blocked. A FLT-1/hERG1/β1 complex was also observed in primary AML blasts, obtained from a population of human patients. The co-expression of FLT-1 and hERG1 conferred a pro-migratory phenotype to AML blasts. Such a phenotype was also observed in vivo. The hERG1-positive blasts were more efficient in invading the peripheral circulation and the extramedullary sites after engraftment into immunodeficient mice. Moreover, hERG1 expression in leukemia patients correlated with a higher probability of relapse and shorter survival periods. We conclude that in AML, hERG1 channels mediate the FLT-1–dependent cell migration and invasion, and hence confer a greater malignancy.

Sign in / Sign up

Export Citation Format

Share Document