SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus

Burnworth, Bettina; Pippin, Jeff; Karna, Prasanthi; Akakura, Shin; Krofft, Ron; Zhang, Guoqiang; Hudkins, Kelly L.; Alpers, Charles E.; Smith, Kelly D.; Shankland, Stuart J.; Gelman, Irwin H.; Nelson, Peter J.

doi:10.1038/labinvest.2011.199

Cited by 34 publications

(35 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This “sequestration” phenomenon by A-Kinase Anchoring Proteins has been previously proposed in a study of AKAP79 overexpression in HEK293 cells [29]. Furthermore, gravin was shown to reduce FAK phosphorylation through the proposed sequestration of Src [30], and gravin has also been shown to sequester cyclin D1 away from the nucleus [31]. Our findings that PKA activity was reduced in the cytosol may be an important consequence of gravin expression or upregulation in vivo .…”

Section: Discussionsupporting

confidence: 77%

FRET biosensors reveal AKAP-mediated shaping of subcellular PKA activity and a novel mode of Ca2+/PKA crosstalk

Schott

Gonowolo

Maliske

et al. 2016

Cellular Signalling

View full text Add to dashboard Cite

Scaffold proteins play a critical role in cellular homeostasis by anchoring signaling enzymes in close proximity to downstream effectors. In addition to anchoring static enzyme complexes, some scaffold proteins also form dynamic signalosomes that can traffic to different subcellular compartments upon stimulation. Gravin (AKAP12), a multivalent scaffold, anchors PKA and other enzymes to the plasma membrane under basal conditions, but upon [Ca2+]i elevation, is rapidly redistributed to the cytosol. Because gravin redistribution also impacts PKA localization, we postulate that gravin acts as a calcium “switch” that modulates PKA-substrate interactions at the plasma membrane, thus facilitating a novel crosstalk mechanism between Ca2+ and PKA-dependent pathways. To assess this, we measured the impact of gravin-V5/His expression on compartmentalized PKA activity using the FRET biosensor AKAR3 in cultured cells. Upon treatment with forskolin or isoproterenol, cells expressing gravin-V5/His showed elevated levels of plasma membrane PKA activity, but cytosolic PKA activity levels were reduced compared with control cells lacking gravin. This effect required both gravin interaction with PKA and localization at the plasma membrane. Pretreatment with calcium-elevating agents thapsigargin or ATP caused gravin redistribution away from the plasma membrane and prevented gravin from elevating PKA activity levels at the membrane. Importantly, this mode of Ca2+/PKA crosstalk was not observed in cells expressing a gravin mutant that resists calcium-mediated redistribution from the cell periphery. These results reveal that gravin impacts subcellular PKA activity levels through the spatial targeting of PKA, and that calcium elevation modulates downstream β-adrenergic/PKA signaling through gravin redistribution, thus supporting the hypothesis that gravin mediates crosstalk between Ca2+ and PKA-dependent signaling pathways. Based on these results, AKAP localization dynamics may represent an important paradigm for the regulation of cellular signaling networks.

show abstract

Section: Discussionsupporting

confidence: 77%

FRET biosensors reveal AKAP-mediated shaping of subcellular PKA activity and a novel mode of Ca2+/PKA crosstalk

Schott

Gonowolo

Maliske

et al. 2016

Cellular Signalling

View full text Add to dashboard Cite

show abstract

“…18 In our hands, anti-AKAP12 immunofluorescence staining resulted in strong immunostaining of human PECs and some tubular cells (Figure 7). A much weaker staining was observed in tubulointerstitial cells and endothelial cells of glomerular and peritubular capillaries ( Figure 7C).…”

Section: Detecting Pecs In Sclerotic Lesions By Using Akap12 or Anxa3supporting

confidence: 49%

Detection of Activated Parietal Epithelial Cells on the Glomerular Tuft Distinguishes Early Focal Segmental Glomerulosclerosis from Minimal Change Disease

Smeets

Stucker

Wetzels

et al. 2014

The American Journal of Pathology

View full text Add to dashboard Cite

In rodents, parietal epithelial cells (PECs) migrating onto the glomerular tuft participate in the formation of focal segmental glomerulosclerosis (FSGS) lesions. We investigated whether immunohistologic detection of PEC markers in the initial biopsies of human patients with first manifestation of idiopathic nephrotic syndrome with no immune complexes can improve the sensitivity to detect sclerotic lesions compared with standard methods. Ninety-five renal biopsies were stained for claudin-1 (PEC marker), CD44 (activated PECs), and LKIV69 (PEC matrix); 38 had been diagnosed as early primary FSGS and 57 as minimal change disease. PEC markers were detected on the tuft in 87% of the biopsies of patients diagnosed as primary FSGS. PEC markers were detected in FSGS lesions from the earliest stages of disease. In minimal change disease, no PEC activation was observed by immunohistology. However, in 25% of biopsies originally diagnosed as minimal change disease the presence of small lesions indicative of a sclerosing process were detected, which were undetectable on standard periodic acid-Schiff staining, even though only a single histologic section for each PEC marker was evaluated. Staining for LKIV69 detected lesions with the highest sensitivity. Two novel PEC markers A-kinase anchor protein 12 and annexin A3 exhibited similar sensitivity. In summary, detection of PECs on the glomerular tuft by immunostaining improves the differentiation between minimal change disease and primary FSGS and may serve to guide clinical decision making.

show abstract

“…We 21, 27 and others 3, 5, 28–31 have reported that a subset of CD44 stained PECs, migrate from Bowman’s capsule to the glomerular tuft following podocyte injury. In the current study, PECs were identified by staining for PAX8 32 and SSeCKS.…”

Section: Resultsmentioning

confidence: 75%

Activated ERK1/2 increases CD44 in glomerular parietal epithelial cells leading to matrix expansion

Roeder

Barnes

Lee

et al. 2017

Kidney International

View full text Add to dashboard Cite

The glycoprotein CD44 is barely detected in normal mouse and human glomeruli, but is increased in glomerular parietal epithelial cells following podocyte injury in focal segmental glomerulosclerosis (FSGS). To determine the biological role and regulation of CD44 in these cells, we employed an in vivo and in vitro approach. Experimental FSGS was induced in CD44 knockout and wildtype mice with a cytotoxic podocyte antibody. Albuminuria, focal and global glomerulosclerosis (periodic acid-Schiff stain) and collagen IV staining were lower in CD44 knockout compared with wild type mice with FSGS. Parietal epithelial cells had lower migration from Bowman’s capsule to the glomerular tuft in CD44 knockout mice with disease compared with wild type mice. In cultured murine parietal epithelial cells, overexpressing CD44 with a retroviral vector encoding CD44 was accompanied by significantly increased collagen IV expression and parietal epithelial cells migration. Because our results showed de novo co-staining for activated ERK1/2 (pERK) in parietal epithelial cells in experimental FSGS, and also in biopsies from patients with FSGS, two in vitro strategies were employed to prove that pERK regulated CD44 levels. First, mouse parietal epithelial cells were infected with a retroviral vector for the upstream kinase MEK-DD to increase pERK, which was accompanied by increased CD44 levels. Second, in CD44 overexpressing parietal epithelial cells, decreasing pERK with U0126 was accompanied by reduced CD44. Finally, parietal epithelial cell migration was higher in cells with increased and reduced in cells with decreased pERK. Thus, pERK is a regulator of CD44 expression and increased CD44 expression leads to a pro-sclerotic and migratory parietal epithelial cells phenotype.

show abstract

SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus

Cited by 34 publications

References 38 publications

FRET biosensors reveal AKAP-mediated shaping of subcellular PKA activity and a novel mode of Ca2+/PKA crosstalk

FRET biosensors reveal AKAP-mediated shaping of subcellular PKA activity and a novel mode of Ca2+/PKA crosstalk

Detection of Activated Parietal Epithelial Cells on the Glomerular Tuft Distinguishes Early Focal Segmental Glomerulosclerosis from Minimal Change Disease

Activated ERK1/2 increases CD44 in glomerular parietal epithelial cells leading to matrix expansion

Contact Info

Product

Resources

About