IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis

Bartolomé, Rubén A.; Garcia-Palmero, Irene; Torres, Sofía; López-Lucendo, María; Balyasnikova, Irina V.; Casal, J. Ignacio

doi:10.1158/0008-5472.can-14-3650

Cited by 78 publications

(69 citation statements)

References 25 publications

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“…A recent study has shown that CHI3L1 binds to IL-13Rα2, which plays a critical role in its effector responses [4]. It has been also reported that IL-13Rα2 signaling requires a scaffold protein, FAM120A, to activate the FAK and PI3K pathways in colon cancer metastasis [23]. Moreover, IL-13Rα2 utilizes TMEM219 in CHI3L1-induced signaling [19].…”

Section: Discussionmentioning

confidence: 99%

“…IL-13Rα2 is significantly upregulated in a number of human cancers [22–24] and has been successfully applied as therapeutic target of chimeric antigen receptor (CAR)-engineered T cells in a patient with recurrent multifocal glioblastoma [25]. Although it has been suggested that IL13Rα2-triggered activation of the FAK and PI3K/Akt/mTOR pathways was mediated by FAM120A, activation of Src family kinases and Erk1/2 were not affected by FAM120A silencing [23]. More recently, the membrane protein TMEM219 has been identified as a binding partner of IL-13Rα2.…”

Section: Introductionmentioning

confidence: 99%

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Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer

Geng

Pan

Zhao

et al. 2018

J Exp Clin Cancer Res

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BackgroundEnzymatically inactive chitinase-like protein CHI3L1 drives inflammatory response and promotes tumor progression. However, its role in gastric cancer (GC) tumorigenesis and metastasis has not yet been fully elucidated. We determined the significance of CHI3L1 expression in patients with GC. We also explored an as-yet unknown receptor of CHI3L1 and investigated the involved signaling in GC metastasis.MethodsCHI3L1 expression was evaluated by immunoblotting, tissue microarray-based immunohistochemistry analysis (n = 100), and enzyme linked immunosorbent assay (ELISA) (n = 150). The interactions between CD44 and CHI3L1 or Interleukin-13 receptor alpha 2 (IL-13Rα2) were analyzed by co-immunoprecipitation, immunofluorescence co-localization assay, ELISA, and bio-layer interferometry. The roles of CHI3L1/CD44 axis in GC metastasis were investigated in GC cell lines and experimental animal model by gain and loss of function.ResultsCHI3L1 upregulation occurred during GC development, and positively correlated with GC invasion depth, lymph node status, and tumor staging. Mechanically, CHI3L1 binding to CD44 activated Erk and Akt, along with β-catenin signaling by phosphorylating β-catenin at Ser552 and Ser675. CD44 also interacted with IL-13Rα2 to form a complex. Notably, CD44v3 peptide and protein, but not CD44v6 peptide or CD44s protein, bound to both CHI3L1 and IL-13Rα2. Our in vivo and in vitro data further demonstrated that CHI3L1 promoted GC cell proliferation, migration, and metastasis.ConclusionsCHI3L1 binding to CD44v3 activates Erk, Akt, and β-catenin signaling, therefore enhances GC metastasis. CHI3L1 expression is a novel biomarker for the prognosis of GC, and these findings have thus identified CHI3L1/CD44 axis as a vital pathway and potential therapeutic target in GC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0876-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer

Geng

Pan

Zhao

et al. 2018

J Exp Clin Cancer Res

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“…Short term colonization assays were performed as described previously [24]. In brief, mice were euthanized 4 days after inoculation, and RNA was isolated from lungs using TRIzol Reagent (Invitrogen) and retrotranscribed.…”

Section: Methodsmentioning

confidence: 99%

VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers

et al. 2016

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We have investigated the role of vascular-endothelial (VE)-cadherin in melanoma and breast cancer metastasis. We found that VE-cadherin is expressed in highly aggressive melanoma and breast cancer cell lines. Remarkably, inactivation of VEcadherin triggered a significant loss of malignant traits (proliferation, adhesion, invasion and transendothelial migration) in melanoma and breast cancer cells. These effects, except transendothelial migration, were induced by the VE-cadherin RGD motifs. Co-immunoprecipitation experiments demonstrated an interaction between VE-cadherin and α2β1 integrin, with the RGD motifs found to directly affect β1 integrin activation. VE-cadherin-mediated integrin signaling occurred through specific activation of SRC, ERK and JNK, including AKT in melanoma. Knocking down VEcadherin suppressed lung colonization capacity of melanoma or breast cancer cells inoculated in mice, while pre-incubation with VE-cadherin RGD peptides promoted lung metastasis for both cancer types. Finally, an in silico study revealed the association of high VE-cadherin expression with poor survival in a subset of melanoma patients and breast cancer patients showing low CD34 expression. These findings support a general role for VE-cadherin and other RGD cadherins as critical regulators of lung and liver metastasis in multiple solid tumours. These results pave the way for cadherin-specific RGD targeted therapies to control disseminated metastasis in multiple cancers.

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“…Lyn, as a negative regulator of allergen-stimulated bone marrow-derived mast cells, regulated the expression of the IL-13 gene (Hernandez-Hansen et al, 2005). The binding of IL-13 triggers the recruitment of several molecules, such as PI3K, Akt, and Src kinase, and enables activation of PI3K (Bartolome et al, 2015). We further found that Lyn overexpression significantly repressed IL-13 expression in the lungs of mice exposed to OVA.…”

Section: Discussionmentioning

confidence: 99%

Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma

Wang

Yang

et al. 2017

EBioMedicine

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In asthma, mucus hypersecretion is thought to be a prominent pathological feature associated with widespread mucus plugging. However, the current treatments for mucus hypersecretion are often ineffective or temporary. The potential therapeutic targets of mucus hypersecretion in asthma remain unknown. Here, we show that Lyn is a central effector of endoplasmic reticulum stress (ER stress) and mucous hypersecretion in asthma. In Lyn-transgenic mice (Lyn-TG) and wild-type (WT) C57BL/6J mice exposed to ovalbumin (OVA), Lyn overexpression attenuates mucus hypersecretion and ER stress. Interleukin 13 (IL-13) induced MUC5AC expression by enhancing ER stress in vitro. Lyn serves as a negative regulator of IL-13-induced ER stress and MUC5AC expression. We further find that an inhibitor of ER stress, which is likely involved in the PI3K p85α/Akt pathway and NFκB activity, blocked MUC5AC expression in Lyn-knockdown cells. Furthermore, PI3K/Akt signaling is required for IL-13-induced ER stress and MUC5AC expression in airway epithelial cells. The ER stress regulation of MUC5AC expression depends on NFκB in Lyn-knockdown airway epithelial cells. Our studies indicate not only a concept of mucus hypersecretion in asthma that involves Lyn kinase but also an important therapeutic candidate for asthma.

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IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis

Cited by 78 publications

References 25 publications

Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer

Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer

VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers

Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma

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