Control of cell adhesion and migration by podocalyxin. Implication of Rac1 and Cdc42

Fernández, Darío; Horrillo, Angélica; Alquézar, Carolina; González-Manchón, Consuelo; Parrilla, Roberto L.; Ayuso, Matilde Sánchez

doi:10.1016/j.bbrc.2013.01.112

Cited by 18 publications

(16 citation statements)

References 29 publications

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“…In a previous study using podocyte-specific Cdc42, Rac1, and RhoA knockout mice, the physiological importance of Cdc42, but not Rac1 or RhoA, in podocytes was shown [55]. Further, the reorganization of the cytoskeletal network mediated by Rac1 and Cdc42 plays a primary role in the cellular responses to podocyte-specific proteins [56]. Rac1 and Cdc42 have been shown to have the opposite function to RhoA in podocytes [57].…”

Section: Discussionmentioning

confidence: 98%

Podocyte Injury Caused by Indoxyl Sulfate, a Uremic Toxin and Aryl-Hydrocarbon Receptor Ligand

et al. 2014

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Indoxyl sulfate is a uremic toxin and a ligand of the aryl-hydrocarbon receptor (AhR), a transcriptional regulator. Elevated serum indoxyl sulfate levels may contribute to progressive kidney disease and associated vascular disease. We asked whether indoxyl sulfate injures podocytes in vivo and in vitro. Mice exposed to indoxyl sulfate for 8 w exhibited prominent tubulointerstitial lesions with vascular damage. Indoxyl sulfate-exposed mice with microalbuminuria showed ischemic changes, while more severely affected mice showed increased mesangial matrix, segmental solidification, and mesangiolysis. In normal mouse kidneys, AhR was predominantly localized to the podocyte nuclei. In mice exposed to indoxyl sulfate for 2 h, isolated glomeruli manifested increased Cyp1a1 expression, indicating AhR activation. After 8 w of indoxyl sulfate, podocytes showed foot process effacement, cytoplasmic vacuoles, and a focal granular and wrinkled pattern of podocin and synaptopodin expression. Furthermore, vimentin and AhR expression in the glomerulus was increased in the indoxyl sulfate-exposed glomeruli compared to controls. Glomerular expression of characteristic podocyte mRNAs was decreased, including Actn4, Cd2ap, Myh9, Nphs1, Nphs2, Podxl, Synpo, and Wt1. In vitro, immortalized-mouse podocytes exhibited AhR nuclear translocation beginning 30 min after 1 mM indoxyl sulfate exposure, and there was increased phospho-Rac1/Cdc42 at 2 h. After exposure to indoxyl sulfate for 24 h, mouse podocytes exhibited a pro-inflammatory phenotype, perturbed actin cytoskeleton, decreased expression of podocyte-specific genes, and decreased cell viability. In immortalized human podocytes, indoxyl sulfate treatment caused cell injury, decreased mRNA expression of podocyte-specific proteins, as well as integrins, collagens, cytoskeletal proteins, and bone morphogenetic proteins, and increased cytokine and chemokine expression. We propose that basal levels of AhR activity regulate podocyte function under normal conditions, and that increased activation of podocyte AhR by indoxyl sulfate contributes to progressive glomerular injury.

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Section: Discussionmentioning

confidence: 98%

Podocyte Injury Caused by Indoxyl Sulfate, a Uremic Toxin and Aryl-Hydrocarbon Receptor Ligand

et al. 2014

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“…The structure of PODXL consists of an N-terminal extracellular domain with extensive N-and O-glycosylation and sialylation, and a cytoplasmic intracellular tail with a C-terminal DTHL consensus sequence capable of interacting with PDZ binding domain (13). The cytoplasmic tail of PODXL, despite its small size, has been reported to interact with proteins such as ezrin (8,14) and Na (þ)/H(þ) exchange regulatory cofactor (NHERF) 1 or 2 (15,16) to activate downstream intracellular signaling, primarily via the PI3K (17), RhoA (15), and Rac1 (8) pathways, leading to epithelial-mesenchymal transition (18), migration (19), and invasion (20).…”

Section: Introductionmentioning

confidence: 99%

A Direct Podocalyxin–Dynamin-2 Interaction Regulates Cytoskeletal Dynamics to Promote Migration and Metastasis in Pancreatic Cancer Cells

et al. 2019

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The sialoglycoprotein podocalyxin is absent in normal pancreas but is overexpressed in pancreatic cancer and is associated with poor clinical outcome. Here, we investigate the role of podocalyxin in migration and metastasis of pancreatic adenocarcinomas using SW1990 and Pa03c as cell models. Although ezrin is regarded as a cytoplasmic binding partner of podocalyxin that regulates actin polymerization via Rac1 or RhoA, we did not detect podocalyxin-ezrin association in pancreatic cancer cells. Moreover, depletion of podocalyxin did not alter actin dynamics or modulate Rac1 and RhoA activities in pancreatic cancer cells. Using mass spectrometry, bioinformatics analysis, coimmunoprecipitation, and pull-down assays, we discovered a novel, direct binding interaction between the cytoplasmic tail of podocalyxin and the large GTPase dynamin-2 at its GTPase, middle, and pleckstrin homology domains. This podocalyxin-dynamin-2 interaction regulated microtubule growth rate, which in turn modulated focal adhesion dynamics and ultimately promoted efficient pancreatic cancer cell migration via microtubule-and Src-dependent pathways. Depletion of podocalyxin in a hemispleen mouse model of pancreatic cancer diminished liver metastasis without altering primary tumor size. Collectively, these findings reveal a novel mechanism by which podocalyxin facilitates pancreatic cancer cell migration and metastasis. Significance: These findings reveal that a novel interaction between podocalyxin and dynamin-2 promotes migration and metastasis of pancreatic cancer cells by regulating microtubule and focal adhesion dynamics.

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“…Bcam and Podxl are cell surface glycoproteins which belong to immunoglobulin superfamily and CD34 family, respectively [25,26]. They are known to mediate interactions between various adhesion molecules and thus regulate cell migration [21,22]. Fzd6 and Wnt7a belonging to the Wnt pathway, act as a Wnt receptor and a ligand, respectively [27].…”

Section: Discussionmentioning

confidence: 99%

“…The results of previous studies have implicated Bcam, Fzd6, Ddr1, and Podxl in cell proliferation and migration in other cell types [21][22][23][24]. Therefore, we assessed effect of miR-199a-5p in the migration and proliferation of keratinocytes to determine the biological function(s) of miR-199a-5p in this cell type.…”

Section: Mir-199a-5p Inhibits Migration But Not Proliferation Of Mousmentioning

confidence: 96%

Identification of miR-199a-5p target genes in the skin keratinocyte and their expression in cutaneous squamous cell carcinoma

Kim

Yoon

2015

Journal of Dermatological Science

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Control of cell adhesion and migration by podocalyxin. Implication of Rac1 and Cdc42

Cited by 18 publications

References 29 publications

Podocyte Injury Caused by Indoxyl Sulfate, a Uremic Toxin and Aryl-Hydrocarbon Receptor Ligand

Podocyte Injury Caused by Indoxyl Sulfate, a Uremic Toxin and Aryl-Hydrocarbon Receptor Ligand

A Direct Podocalyxin–Dynamin-2 Interaction Regulates Cytoskeletal Dynamics to Promote Migration and Metastasis in Pancreatic Cancer Cells

Identification of miR-199a-5p target genes in the skin keratinocyte and their expression in cutaneous squamous cell carcinoma

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