Kindlin-2 regulates renal tubular cell plasticity by activation of Ras and its downstream signaling

Wei, Xiaofan; Wang, Xiang; Yang, Xia; Tang, Yan; Feng, Liang; Fang, Wei‐Gang; Zhang, Hongquan

doi:10.1152/ajprenal.00499.2013

Cited by 32 publications

(24 citation statements)

References 54 publications

(56 reference statements)

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“…We also proved that activated Ras can markedly rescue RNA Pol I activity during defective integrin signaling, demonstrating the critical role of Ras in the whole process. There is a previous report demonstrating that kindlin-2 promotes Ras activation and its downstream signaling (34). Our study confirms the critical role of Ras in kindlin-2 signaling.…”

Section: Discussionsupporting

confidence: 90%

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

You

et al. 2016

Molecular and Cellular Biology

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c RNA polymerase I-mediated rRNA production is a key determinant of cell growth. Despite extensive studies, the signaling pathways that control RNA polymerase I-mediated rRNA production are not well understood. Here we provide original evidence showing that RNA polymerase I transcriptional activity is tightly controlled by integrin signaling. Furthermore, we show that a signaling axis consisting of focal adhesion kinase (FAK), Src, phosphatidylinositol 3-kinase (PI3K), Akt, and mTOR mediates the effect of integrin signaling on rRNA transcription. Additionally, we show that in kindlin-2 knockout mouse embryonic fibroblasts, overactivation of Ras, Akt, and Src can successfully rescue the defective RNA polymerase I activity induced by the loss of kindlin-2. Finally, through experiments with inhibitors of FAK, Src, and PI3K and rescue experiments in MEFs, we found that the FAK/Src/PI3K/Akt signaling pathway to control rRNA transcription is linear. Collectively, these studies reveal, for the first time, a pivotal role of integrin signaling in regulation of RNA polymerase I transcriptional activity and shed light on the downstream signaling axis that participates in regulation of this key aspect of cell growth. RNA polymerase I (Pol I) plays a central role in regulating cellular growth and proliferation (1). Eukaryotic cells contain hundreds of ribosomal DNA (rDNA) copies that occupy several different chromosomal locations (2). The production of rRNA can be divided into several steps, i.e., rRNA transcription, modification, and processing, all of which occur in the nucleolus (3, 4). The rate-limiting step is rRNA transcription (1, 5). On sensing of outside stimuli, a preinitiation complex comprised of the transcriptional factors upstream binding factor (UBF), SL1, TBP, Rrn3, and TTF assembles in the promoter region of rDNA. This complex then recruits RNA polymerase I to rDNA loci, and rRNA transcription starts (6-8). In mammalian cells, a single precursor rRNA transcript, 47S rRNA (14.3 kb), is transcribed from rDNA by the RNA polymerase I complex. This large polycistronic transcript encompasses 18S, 5.8S, and 28S rRNAs and includes several spacer regions, which are later processed into distinct rRNA species before assembly into preribosomal subunits (9).The transcriptional activity of Pol I is a fundamental determinant of cell proliferation capacity (3). In rapidly proliferating cells, rRNA production takes more than 50% of all nuclear transcriptional activity. In yeast cells, this percentage can reach more than 80% (10). As such, the tremendous energy consumption demands tight control.At the tissue level, cells attach to the extracellular matrix (ECM) through cell surface receptors termed integrins (11). Integrins are heterodimeric transmembrane receptors comprised of ␣ subunits and ␤ subunits that bind to extracellular ligands, such as laminin, collagen, vitronectin, and fibronectin. Different combinations of the 18 ␣ subunits and 8 ␤ subunits confer specificity on the integrin-ECM interactions (12). After binding ...

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Section: Discussionsupporting

confidence: 90%

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

You

et al. 2016

Molecular and Cellular Biology

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“…We have already reported that H-Ras isoform is able to modulate renal fibrosis and myofibroblast activation following ureteral obstruction in mice [24, 27]. Notably Ras activation has been shown to be involved in EMT of tubular cells to myofibroblasts [49], and specifically H-Ras is involved in TGF- β 1-induced EMT [50]. In the kidney, chaetomellic acid A selectively inhibits the membrane-bound of H-Ras without affecting the membrane-bound of Ki-Ras or other prenylated intracellular proteins like Rab [51].…”

Section: Discussionmentioning

confidence: 99%

Effect of Angiotensin II and Small GTPase Ras Signaling Pathway Inhibition on Early Renal Changes in a Murine Model of Obstructive Nephropathy

Rodríguez-Peña

Fuentes-Calvo

Docherty

et al. 2014

BioMed Research International

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Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO. Animals either received angiotensin II or underwent UUO. UUO animals received either losartan, atorvastatin, and farnesyl transferase inhibitor (FTI) L-744,832, or chaetomellic acid A (ChA). Levels of activated Ras, phospho-ERK1/2, phospho-Akt, fibronectin, and α-smooth muscle actin were subsequently quantified in renal tissue by ELISA, Western blot, and/or immunohistochemistry. Our results demonstrate that administration of angiotensin II induces activation of the small GTPase Ras/Erk/Akt signaling system, suggesting an involvement of angiotensin II in the early obstruction-induced activation of renal Ras. Furthermore, upstream inhibition of Ras signalling by blocking either angiotensin AT1 type receptor or by inhibiting Ras prenylation (atorvastatin, FTI o ChA) reduced the activation of the Ras/Erk/Akt signaling system and decreased the early fibrotic response in the obstructed kidney. This study points out that pharmacological inhibition of Ras activation may hold promise as a future strategy in the prevention of renal fibrosis.

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“…In affected mouse and human tubular epithelial cells, kindlin-2 is highly expressed and promotes EMT by increasing Erk1/2, Akt and TGFβ signaling. It has been demonstrated that kindlin-2 induces Ras activation through the recruitment of Son of sevenless homolog 1 (Sos1), which, subsequently, activates Erk1/2 and Akt signaling (Wei et al, 2014). Furthermore, kindlin-2 has been shown to activate the TGFβ signaling pathway through direct binding of its C-terminal FERM domain to transforming growth factor β receptor I (TβRI; also known as TGFBR1) and of its N-terminus to Smad3 (Wei et al, 2013).…”

Section: Kindlin-2 Is Involved In Multiple Diseasesmentioning

confidence: 99%

The kindlin family: functions, signaling properties and implications for human disease

Rognoni

Ruppert

Fässler

2016

Journal of Cell Science

192

186

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The kindlin (or fermitin) family of proteins comprises three members (kindlin-1,-2 and -3) of evolutionarily conserved focal adhesion (FA) proteins, whose best-known task is to increase integrin affinity for a ligand (also referred as integrin activation) through binding of β-integrin tails. The consequence of kindlin-mediated integrin activation and integrin-ligand binding is cell adhesion, spreading and migration, assembly of the extracellular matrix (ECM), cell survival, proliferation and differentiation.

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Kindlin-2 regulates renal tubular cell plasticity by activation of Ras and its downstream signaling

Abstract: regulates renal tubular cell plasticity by activation of Ras and its downstream signaling.

Cited by 32 publications

References 54 publications

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

Effect of Angiotensin II and Small GTPase Ras Signaling Pathway Inhibition on Early Renal Changes in a Murine Model of Obstructive Nephropathy

The kindlin family: functions, signaling properties and implications for human disease

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