A feedback regulation between Kindlin‐2 and GLI1 in prostate cancer cells

Gao, Jianchao; Khan, Ammad Aslam; Shimokawa, Tetsuya; Zhan, Jun; Strömblad, Staffan; Fang, Wei; Zhang, Hongquan

doi:10.1016/j.febslet.2012.12.028

Cited by 25 publications

(15 citation statements)

References 30 publications

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“…Several lines of evidence support TGFβ signaling induction of Gli, independent of Hh signaling [17, 25, 26]. We examined the role of TGF-β on the regulation of Gli2 and PTHrP and found that TGFβ stimulation significantly increased levels of PTHrP expression (Figure 4A & 4B).…”

Section: Resultsmentioning

confidence: 83%

Hedgehog and TGFβ signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma

et al. 2016

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Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC invasion into the lymph nodes and mandible correlates with increased rates of recurrence and lower overall survival. Tumors that infiltrate mandibular bone proliferate rapidly and induce bone destruction. While survival rates have increased 12% over the last 20 years, this improvement is attributed to general advances in prevention, earlier detection, and updated treatments. Additionally, despite decades of research, the molecular mechanisms of OSCC invasion into the mandible are not well understood. Parathyroid Hormone-related Protein (PTHrP), has been shown to be essential for mandibular invasion in OSCC animal models, and our previous studies demonstrate that the transcription factor Gli2 increases PTHrP expression in tumor metastasis to bone. In OSCC, we investigated regulators of Gli2, including Hedgehog, TGFβ, and Wnt signaling to elucidate how PTHrP expression is controlled. Here we show that canonical Hedgehog and TGFβ signaling cooperate to increase PTHrP expression and mandibular invasion in a Gli2-dependent manner. Additionally, in an orthotopic model of mandibular invasion, inhibition of Gli2 using shRNA resulted in a significant decrease of both PTHrP expression and bony invasion. Collectively, our findings demonstrate that multiple signaling pathways converge on Gli2 to mediate PTHrP expression and bony invasion, highlighting Gli2 as a therapeutic target to prevent bony invasion in OSCC.

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Section: Resultsmentioning

confidence: 83%

Hedgehog and TGFβ signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma

et al. 2016

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“…Interestingly, in esophageal SCC, kindlin-2 itself might be a target for miR-200b, resulting in decreased kindlin-2 levels and tumor cell invasion . In addition to regulation of EMT and invasion, kindlin-2 has been shown to promote cell survival through stimulation of Hedgehog signaling by inducing the expression of Loss of expression increases cell invasion EMMPRIN regulates kindlin-3 and β1 integrin expression Delyon et al, 2015 Gli1 and anti-apoptotic Bcl2 proteins (Gao et al, 2013;Gong et al, 2010;Shen et al, 2013). Kindlin-2 has also suggested to enhance genome instability, a hallmark of cancer formation, although it is not clear how this is achieved at the molecular level (Zhao 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

200

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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“…However, until now less is known about the mechanisms underlying Kindlin‐2 regulation on integrin‐mediated outside‐in signaling. In addition to the regulation of the integrin‐mediated signaling, Kindlin‐2 was also reported to be involved in a variety of other signaling pathways, including Wnt/β‐catenin [26], TGF‐β [27] and SHH signaling pathways [28].…”

Section: Introductionmentioning

confidence: 99%

Kindlin‐2 phosphorylation by Src at Y193 enhances Src activity and is involved in Migfilin recruitment to the focal adhesions

Liu

Wang

et al. 2015

FEBS Letters

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a b s t r a c tKindlin-2 regulates external to internal cell signaling by interaction with integrins in a process that involves the tyrosine kinase, Src. However, the underlying mechanisms remain elusive. Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. These findings suggest that Src, Kindlin-2 and Migfilin together constitute a positive feedback loop that controls Src activity and regulates integrin-mediated cellular functions.

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A feedback regulation between Kindlin‐2 and GLI1 in prostate cancer cells

Cited by 25 publications

References 30 publications

Hedgehog and TGFβ signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma

Hedgehog and TGFβ signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma

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

Kindlin‐2 phosphorylation by Src at Y193 enhances Src activity and is involved in Migfilin recruitment to the focal adhesions

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