Integrin α6β4 Promotes Autocrine Epidermal Growth Factor Receptor (EGFR) Signaling to Stimulate Migration and Invasion toward Hepatocyte Growth Factor (HGF)

Carpenter, Brittany L.; Chen, Min; Knifley, Teresa; Davis, Kelley A.; Harrison, Susan M.; Stewart, Rachel L.; O’Connor, Kathleen L.

doi:10.1074/jbc.m115.686873

Cited by 29 publications

(31 citation statements)

References 56 publications

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“…These results are in agreement with previous studies demonstrating the association of TMEM16A expression with the EGFR signaling pathway in breast cancer and HNSCC (11,12,22). Given that the EGFR signaling pathway in pancreatic cancer relies on the EGFR ligands (13,14) and promotes pancreatic ductal adenocarcinoma (PDAC) development by regulating acinar-ductal metaplasia, cancer cell migration, and the occurrence of metastasis (15,17,18,23), our finding suggests that TMEM16A could play an essential role in ligand-induced EGFR signaling pathway in pancreatic cancer.…”

Section: Tmem16a Is Overexpressed In Pancreatic Ductal Adenocarcinomasupporting

confidence: 93%

“…In pancreatic cancer, the EGFR signaling pathway is involved in both cancer initiation and the development of metastasis (13,14). Unlike breast cancer and HNSCC that are associated with mutations rendering EGFR constitutively active, pancreatic cancer involves activation of the EGFR signaling pathway by extracellular ligands such as EGF, TGF-α, or Epiregulin (15)(16)(17)(18). It is therefore important to determine whether TMEM16A regulates EGFR signaling in pancreatic cancer cells in a manner that depends on ligand activation of EGFR.…”

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confidence: 99%

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TMEM16A controls EGF-induced calcium signaling implicated in pancreatic cancer prognosis

Crottès

Lin

Peters

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceCancer of the pancreas is highly heterogeneous. Improvement of diagnosis and prognosis requires the discovery of new biomarkers and new methods of classification. In this study, we identify TMEM16A calcium-activated chloride channel as a potential key biomarker for pancreatic cancer. We demonstrate that, through the modulation of chloride homeostasis and the initiation of a calcium signaling pathway, TMEM16A is an important regulator of ligand-induced EGFR signaling in pancreatic cancer cells. Taken together, our findings establish that EGF-induced TMEM16A-dependent calcium pathways constitute a gene set sufficient for classification of pancreatic cancer, and provide inroads for molecular characterization of different subtypes of pancreatic cancer.

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Section: Tmem16a Is Overexpressed In Pancreatic Ductal Adenocarcinomasupporting

confidence: 93%

mentioning

confidence: 99%

TMEM16A controls EGF-induced calcium signaling implicated in pancreatic cancer prognosis

Crottès

Lin

Peters

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…In particular, integrin β4 has been shown to interact with EGFR in lipid rafts where it enhances cell growth and proliferation [34]. Furthermore, our lab has demonstrated that in pancreatic carcinoma cells, integrin α6β4 promotes autocrine EGFR signaling [35]. …”

Section: Discussionmentioning

confidence: 99%

Elevated integrin α6β4 expression is associated with venous invasion and decreased overall survival in non–small cell lung cancer

et al. 2016

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Lung cancer carries a poor prognosis and is the most common cause of cancer-related death worldwide. The integrin α6β4, a laminin receptor, promotes carcinoma progression in part by cooperating with various growth factor receptors to facilitate invasion and metastasis. In carcinoma cells with mutant TP53, the integrin α6β4 promotes cell survival. TP53 mutations and integrin α6β4 overexpression co-occur in many aggressive malignancies. Due to the high frequency of TP53 mutations in lung squamous cell carcinoma (SCC), we sought to investigate the association of integrin β4 expression with clinicopathologic features and survival in non-small cell lung cancer (NSCLC). We constructed a lung cancer tissue microarray and stained sections for integrin β4 subunit expression using immunohistochemistry. We found that integrin β4 expression is elevated in SCC compared to adenocarcinoma (P<0.0001), which was confirmed in external gene expression datasets (P<0.0001). We also determined that integrin β4 overexpression associates with the presence of venous invasion (P=0.0048), and with reduced overall patient survival (Hazard ratio 1.46, 95% confidence interval 1.01 to 2.09, P=0.0422). Elevated integrin β4 expression was also shown to associate with reduced overall survival in lung cancer gene expression datasets (Hazard ratio 1.49, 95% confidence interval 1.31 to 1.69, P<0.0001). Using cBioPortal, we generated a network map demonstrating the 50 most highly altered genes neighboring ITGB4 in SCC which included laminins, collagens, CD151, genes in the EGFR and PI3K pathways, and other known signaling partners. In conclusion, we demonstrate that integrin β4 is overexpressed in NSCLC where it is an adverse prognostic marker.

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“…Activation of EGFR would activate variable signaling pathways after its activation such as PI3-kinase-, Rac1-and MAPK-dependent pathways by coupling ErbB2 receptor [44], which have the stimulatory or inhibitory action on the ENaC-mediated Na + transport. Further, the EGFR stimulation connects with hepatocyte growth factor [51]. The substrate of hepatocyte growth factorregulated tyrosine substance (Hrs) is involved in the endosomal membrane trafficking [52], and Hrs binds ENaC controlling the intracellular ENaC trafficking [53].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Action of Protein Tyrosine Kinase Inhibitors on the Hypotonicity-Stimulated Trafficking Kinetics of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells: Analysis Using a Mathematical Model

Marunaka

Taruno

Yamamoto

et al. 2018

Cell Physiol Biochem

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Background/Aims: Epithelial Na₊ channels (ENaCs) play crucial roles in control of blood pressure by determining the total amount of renal Na₊ reabsorption, which is regulated by various factors such as aldosterone, vasopressin, insulin and osmolality. The intracellular trafficking process of ENaCs regulates the amount of the ENaC-mediated Na₊ reabsorption in the collecting duct of the kidney mainly by determining the number of ENaC expressed at the apical membrane of epithelial cells. Although we previously reported protein tyrosine kinases (PTKs) contributed to the ENaC-mediated epithelial Na₊ reabsorption, we have no information on the role of PTKs in the intracellular ENaC trafficking. Methods: Using the mathematical model recently established in our laboratory, we studied the effect of PTKs inhibitors (PTKIs), AG1296 (10 µM: an inhibitor of the PDGF receptor (PDGFR)) and AG1478 (10 µM: an inhibitor of the EGF receptor (EGFR)) on the rates of the intracellular ENaC trafficking in renal epithelial A6 cells endogenously expressing ENaCs. Results: We found that application of PTKIs significantly reduced the insertion rate of ENaC to the apical membrane by 56%, the recycling rate of ENaC by 83%, the cumulative time of an individual ENaC staying in the apical membrane by 27%, the whole life-time after the first insertion of ENaC by 47%, and the cumulative Na₊ absorption by 61%, while the degradation rate was increased to 3.8-fold by application of PTKIs. These observations indicate that PTKs contribute to the processes of insertion, recycling and degradation of ENaC in the intracellular trafficking process under a hypotonic condition. Conclusion: The present study indicates that application of EGFR and PDGFR-inhibitable PTKIs reduced the insertion rate (k_I), and the recycling rate (k_R) of ENaCs, but increased degradation rate (k_D) in renal A6 epithelial cells under a hypotonic condition. These observations indicate that hypotonicity increases the surface expression of ENaCs by increasing the insertion rate (k_I) and the recycling rate (k_R) of ENaCs associated with a decrease in the degradation rate but without any significant effects on the endocytotic rate (k_E) in EGFR and PDGFR-related PTKs-mediated pathways.

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Integrin α6β4 Promotes Autocrine Epidermal Growth Factor Receptor (EGFR) Signaling to Stimulate Migration and Invasion toward Hepatocyte Growth Factor (HGF)

Cited by 29 publications

References 56 publications

TMEM16A controls EGF-induced calcium signaling implicated in pancreatic cancer prognosis

TMEM16A controls EGF-induced calcium signaling implicated in pancreatic cancer prognosis

Elevated integrin α6β4 expression is associated with venous invasion and decreased overall survival in non–small cell lung cancer

Action of Protein Tyrosine Kinase Inhibitors on the Hypotonicity-Stimulated Trafficking Kinetics of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells: Analysis Using a Mathematical Model

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