CCN2 Increases TGF-β Receptor Type II Expression in Vascular Smooth Muscle Cells: Essential Role of CCN2 in the TGF-β Pathway Regulation

Tejera‐Muñoz, Antonio; Márquez‐Expósito, Laura; Tejedor-Santamaría, Lucía; Rayego‐Mateos, Sandra; Orejudo, Macarena; Suárez-Álvarez, Beatriz; López‐Larrea, Carlos; Ruíz-Ortega, Marta; Rodrigues-Díez, Raúl R.

doi:10.3390/ijms23010375

Cited by 5 publications

(3 citation statements)

References 75 publications

(94 reference statements)

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“… 17 These would suggest the possible expansion of fibroblasts and with it the ability to lay down additional ECM (consistent with the Masson trichrome staining), while the NTPD2 population may be diminishing or phenoconverting. The lack of change in Hif1α, Tgfβ, and Ccn2 suggests the tissue is neither hypoxic nor experiencing inflammation, 18 while the lack of change in ki67 indicates that cells in the BSM are not proliferating. On balance, the picture presented suggests that myocytes in BSM are undergoing a phenotypic transition away from a contractile state to one that is more synthetic.…”

Section: Resultsmentioning

confidence: 99%

Deletion of Mechanosensory β1-integrin From Bladder Smooth Muscle Results in Voiding Dysfunction and Tissue Remodeling

MacIver

Zhang

et al. 2022

Function

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The bladder undergoes large shape changes as it fills and empties and experiences complex mechanical forces. These forces become abnormal in diseases of the lower urinary tract such as overactive bladder, neurogenic bladder and urinary retention. As the primary mechanosensors linking the actin cytoskeleton to the extracellular matrix (ECM), integrins are likely to play vital roles in maintaining bladder smooth muscle (BSM) homeostasis. In a tamoxifen-inducible smooth muscle conditional knockout of β1-integrin there was concomitant loss of α1- and α3-integrins from BSM and upregulation of αV- and β3-integrins. Masson's staining showed a reduction in smooth muscle with an increase in collagenous ECM. Functionally mice exhibited a changing pattern of urination by voiding spot assay up to eight weeks after tamoxifen. By eight weeks there was increased frequency with reductions in voided volume, consistent with overactivity. Cystometrograms confirmed there was a significant reduction in intercontractile interval with reduced maximal bladder pressure. Muscle strip myography revealed a loss of contraction force in response to electrical field stimulation, that was entirely due to loss of muscarinic contractility. Quantitative western blotting showed a loss of M3 receptor and no change in P2X1. qPCR on extracellular matrix and interstitial genes revealed loss of Ntpd2, a marker of an interstitial cell subpopulation; and an upregulation of S100A4 which is often associated with fibroblasts. Collectively, the data show that loss of appropriate mechanosensation through integrins results in cellular and extracellular remodeling, and concomitant bladder dysfunction that resembles lower urinary tract symptoms seen in older people.

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Section: Resultsmentioning

confidence: 99%

Deletion of Mechanosensory β1-integrin From Bladder Smooth Muscle Results in Voiding Dysfunction and Tissue Remodeling

MacIver

Zhang

et al. 2022

Function

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“…An additional intriguing finding in the context of cancer signaling that emerged from the global proteomics analysis is the upregulation of AP‐1 transcription, TGFBR ligand TGFB1 and the CCN family of proteins in ROS1 D2113N cells. Previous literature has demonstrated a connection between TGFβ upregulation and AP‐1 transcription (Derynck et al , 2021 ), as well as the upregulation of CCN proteins by TGFβ (Nakerakanti et al , 2011 ; Tejera‐Muñoz et al , 2021 ). Both TGFβ and the CCN family of proteins have been implicated in poorer prognosis in cancer due to their ability to promote stem cell‐like behavior, decrease cell adhesion, increase invasiveness and metastatic potential, and induce angiogenesis across a wide range of cancer types (Massagué, 2008 ; Haque et al , 2011 ; Lau, 2012 ; Kim et al , 2018 ).…”

Section: Discussionmentioning

confidence: 95%

Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors

Iyer,

Nusser,

Jones

et al. 2023

EMBO Mol Med

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ROS1 is the largest receptor tyrosine kinase in the human genome. Rearrangements of the ROS1 gene result in oncogenic ROS1 kinase fusion proteins that are currently the only validated biomarkers for targeted therapy with ROS1 TKIs in patients. While numerous somatic missense mutations in ROS1 exist in the cancer genome, their impact on catalytic activity and pathogenic potential is unknown. We interrogated the AACR Genie database and identified 34 missense mutations in the ROS1 tyrosine kinase domain for further analysis. Our experiments revealed that these mutations have varying effects on ROS1 kinase function, ranging from complete loss to significantly increased catalytic activity. Notably, Asn and Gly substitutions at Asp2113 in the ROS1 kinase domain were found to be TKI‐sensitive oncogenic variants in cell‐based model systems. In vivo experiments showed that ROS1 D2113N induced tumor formation that was sensitive to crizotinib and lorlatinib, FDA‐approved ROS1‐TKIs. Collectively, these findings highlight the tumorigenic potential of specific point mutations within the ROS1 kinase domain and their potential as therapeutic targets with FDA‐approved ROS1‐TKIs.

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“…Another unexpected finding, in comparison to ROS1 fusions is the upregulation of TGFBR ligand TGFB1, and the CCN family of proteins. Previous literature has demonstrated the link between activation of JNK family kinases and AP-1 transcriptional activity (Karin, 1995), of TGFβ upregulation by AP-1 transcription (Derynck et al , 2021), and notably, upregulation of CCN proteins by TGFβ (Nakerakanti et al , 2011; Tejera-Muñoz et al , 2021). Both TGFβ and the CCN family of proteins are linked to poorer prognosis in cancer through their effects on promoting stem cell-like behavior, decreased cell adhesion, and angiogenesis in diverse cancer types (Haque et al , 2011; Lau, 2012; Massagué, 2008).…”

Section: Discussionmentioning

confidence: 99%

Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors

Iyer

Nusser

Jones

et al. 2022

Preprint

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ROS1 encodes the largest receptor tyrosine kinase (RTK) in the human genome. Chromosomal rearrangements of ROS1 generate oncogenic kinase fusion proteins sensitive to inhibition by tyrosine kinase inhibitors (TKIs). To date, ROS1 fusions are the only validated biomarkers for therapeutic implementation of ROS1 TKIs. While the cancer genome reveals nonsynonymous missense mutations in ROS1, the impact of these mutations on catalytic activity or pathogenic potential is unknown. We queried the AACR Genie database for ROS1 aberrations and nominated thirty-four non-synonymous missense mutations residing in the ROS1 tyrosine kinase domain for functional interrogation. Immunoblotting revealed diverse impact of the mutations on kinase function, ranging from loss of function to significant increase in catalytic activity. Notably, Asp and Gly substitutions at the D2113 position within the ROS1 kinase domain dramatically increased autophosphorylation and phosphorylation of downstream effectors. ROS1 D2113N/G were ROS1 TKI-sensitive, transformative oncogenes in independent cell models. Molecular dynamic simulations revealed drastic local alterations in the activation loop of of ROS1 D2113N as compared to the wildtype kinase. Global proteomics and phospho-proteomics showed that ROS1 D2113N upregulates phosphorylation of known effectors (e.g., SHP2 and STAT3) akin to ROS1 fusions, but also increases phosphorylation of pathways not previously linked to ROS1, including mTORC2, JNK1/2, AP-1, TGFB1 and CCN1. In vivo, ROS1 D2113N drove tumor formation that was sensitive to inhibition by crizotinib and lorlatinib. Taken together, these data establish that select point mutations within ROS1 RTK drive tumorigenesis and maybe therapeutically targetable with existing FDA-approved ROS1-TKIs.

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CCN2 Increases TGF-β Receptor Type II Expression in Vascular Smooth Muscle Cells: Essential Role of CCN2 in the TGF-β Pathway Regulation

Cited by 5 publications

References 75 publications

Deletion of Mechanosensory β1-integrin From Bladder Smooth Muscle Results in Voiding Dysfunction and Tissue Remodeling

Deletion of Mechanosensory β1-integrin From Bladder Smooth Muscle Results in Voiding Dysfunction and Tissue Remodeling

Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors

Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors

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