Pkd2 Dosage Influences Cellular Repair Responses following Ischemia-Reperfusion Injury

Prasad, Sony; McDaid, John; Tam, Frederick W.K.; Haylor, J.; Ong, Albert

doi:10.2353/ajpath.2009.090227

Cited by 70 publications

(66 citation statements)

References 42 publications

(52 reference statements)

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“…18 Indeed, Src is activated in tubule epithelial cells in response to ischemia reperfusion injury and appears to participate in tubular regeneration. 67 PC1 expression is increased after renal ischemia reperfusion injury, 68 and the cleaved PC1 tail accumulates in tubule epithelial cells in response to ureteral obstruction. 6 Therefore, we speculate that the PC1-p30/Src/STAT3 pathway is normally activated in response to renal insults and integrates signaling inputs (such as EGF and cAMP) to provide a proliferative outcome to facilitate tissue regeneration.…”

Section: Discussionmentioning

confidence: 99%

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Talbot¹,

Song²,

Wang³

et al. 2014

Journal of the American Society of Nephrology

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Polycystin-1 (PC1) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease (ADPKD). The transcription factor STAT3 (signal transducer and activator of transcription 3) was shown to be activated in cyst-lining cells in ADPKD and PKD mouse models and may drive renal cyst growth, but the mechanisms leading to persistent STAT3 activation are unknown. A proteolytic fragment of PC1 corresponding to the cytoplasmic tail, PC1-p30, is overexpressed in ADPKD. Here, we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src, resulting in Srcdependent activation of STAT3 by tyrosine phosphorylation. The PC1-p30-mediated activation of Src/ STAT3 was independent of JAK family kinases and insensitive to the STAT3 inhibitor suppressor of cytokine signaling 3. Signaling by the EGF receptor (EGFR) or cAMP amplified the activation of Src/STAT3 by PC1-p30. Expression of PC1-p30 changed the cellular response to cAMP signaling. In the absence of PC1-p30, cAMP dampened EGFR-or IL-6-dependent activation of STAT3; in the presence of PC1-p30, cAMP amplified Src-dependent activation of STAT3. In the polycystic kidney (PCK) rat model, activation of STAT3 in renal cystic cells depended on vasopressin receptor 2 (V2R) signaling, which increased cAMP levels. Genetic inhibition of vasopressin expression or treatment with a pharmacologic V2R inhibitor strongly suppressed STAT3 activation and reduced renal cyst growth. These results suggest that PC1, via its cleaved cytoplasmic tail, integrates signaling inputs from EGFR and cAMP, resulting in Src-dependent activation of STAT3 and a proliferative response.

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Section: Discussionmentioning

confidence: 99%

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Talbot¹,

Song²,

Wang³

et al. 2014

Journal of the American Society of Nephrology

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“…82 PC1 and PC2 are critical for cellular repair and controlled growth, as well as for division of tubule cells after kidney injury, thus explaining the injury sensitivity of ADPKD kidneys. 83,84 ADPKD leads to kidney enlargement with increasing numbers and size of cysts over time because of abnormal renal epithelial cell growth, together with a disturbed fluid transport resulting in end-stage renal disease in 50% of patients.…”

Section: Autophagy and Ciliummentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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Motile and primary cilia (PC) are microtubule-based structures located at the cell surface of many cell types. Cilia govern cellular functions ranging from motility to integration of mechanical and chemical signaling from the environment. Recent studies highlight the interplay between cilia and autophagy, a conserved cellular process responsible for intracellular degradation. Signaling from the PC recruits the autophagic machinery to trigger autophagosome formation. Conversely, autophagy regulates ciliogenesis by controlling the levels of ciliary proteins. The cross talk between autophagy and ciliated structures is a novel aspect of cell biology with major implications in development, physiology and human pathologies related to defects in cilium function. Cell Death and Differentiation (2015) 22, 389-397; doi:10.1038/cdd.2014.171; published online 31 October 2014 FactsAutophagy is a degradative and recycling mechanism that allows cells to adapt to stress situations including nutrient deprivation. Primary cilia (PC) and motile cilia (MC) are sensory structures at the cell surface. PC sense nutrient, growth factor and calcium changes in the extracellular environment and also respond to mechanical stress. MC are beating structures that contribute to innate defense in the lung, for example. The PC is a site for the recruitment of autophagy-related (ATG) proteins that mediate autophagosome formation in response to cilium-dependent signaling. In turn, autophagy regulates the biogenesis of cilia by degrading certain proteins involved in cilia formation. Modulation of autophagy represents a new therapeutic opportunity in diseases related to defective cilia function. Open QuestionsHow are ATG proteins transported to the PC? How do ATG proteins recruited to the PC contribute to the biogenesis of phagophores and autophagosomes? Ciliary proteins are degraded by autophagy. How selective is this degradative pathway? Do some of these proteins contain motifs that result in selective engulfment by autophagosomes?What are the determinants that switch the degradation of ciliary proteins between basal and induced autophagy? Is there any specific function for cilium-dependent autophagy in ciliated cells? Do signals that trigger cilium-dependent autophagy depend on the stimuli (chemical, mechanical) or do all stimuli converge to a single signaling pathway upstream of the autophagy machinery? Can modulation of autophagy contribute to the restoration of cilium functions?Receptors, transporters and specialized plasma membrane structures such as cilia constitute the interfaces between the extracellular and intracellular milieu and allow the cells to trigger specific responses to adapt to changes imposed by the environment. Among these adaptive responses, macroautophagy (hereafter referred to as 'autophagy') is a catabolic process conserved in eukaryotic cells by which the cell recycles its own constituents. 1 Autophagy is involved in the adaptation to starvation, cell differentiation and development, the degradation of aberrant structure...

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“…13 Both Pkd1 and Pkd2 heterozygotes are especially sensitive to renal injury, resulting in increased inflammation, apoptosis, and fibrosis 18 and hastening the development of microcysts. 19,20 In addition, altered water balance (antidiuresis), with high urine and low plasma osmolality, has been noted in Pkd1 ϩ/Ϫ mice, whereas cells from patients with PKD2 have altered Ca 2ϩ homeostasis. 21 Together, these data indicate that polycystin 1 and 2 are proteins that are sensitive to heterozygous dosage reduction.…”

mentioning

confidence: 99%

What Is the Role of Somatic Mutation in Autosomal Dominant Polycystic Kidney Disease?

Harris

2010

Journal of the American Society of Nephrology

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Pkd2 Dosage Influences Cellular Repair Responses following Ischemia-Reperfusion Injury

Cited by 70 publications

References 42 publications

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Autophagy and regulation of cilia function and assembly

What Is the Role of Somatic Mutation in Autosomal Dominant Polycystic Kidney Disease?

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