Src family kinases, adaptor proteins and the actin cytoskeleton in epithelial-to-mesenchymal transition

Ortiz, María A.; Mikhailova, Tatiana; Li, Xiang; Porter, Baylee A.; Bah, Alaji; Kotula, Leszek

doi:10.1186/s12964-021-00750-x

Cited by 85 publications

(70 citation statements)

References 195 publications

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“…Despite the increase in cell viability during infection, we observed a complete absence of detectible actin filaments suggesting either enhanced depolymerization of Factin or altered actin dynamics. Consequently, BO inhibition of Src activity can lead to actin depolymerization due to retention of alpha and b-catenin at the cell membrane 80,81 .…”

Section: Discussionmentioning

confidence: 99%

Ex Vivo Validation of Six FDA-Approved Non-Receptor Tyrosine Kinase Inhibitors (NRTKIs) as Antivirals to Pandemic and Seasonal Influenza A Viruses

Meineke

Stelz

Busch

et al. 2022

Preprint

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Influenza viruses are important respiratory pathogens that cause substantial morbidity and mortality annually. In addition to seasonal influenza outbreaks, new emerging influenza A viruses (IAV) can cause pandemic influenza outbreaks. Apart from effective vaccines, there is a need for better treatment options to combat infections with these viruses when vaccines are not available or show reduced efficacy (e.g., in immmunocompromised patients). The limited range of licensed antiviral drugs and emergence of drug-resistance mutations highlight the need for novel intervention strategies like host-targeted antivirals. Repurposing FDA-approved kinase inhibitors may offer a fast-track for a new generation of host-targeted antivirals. Small molecule kinase inhibitors (SMKIs) can inhibit replication of viruses and improve survival in vivo; however, no SMKI has been approved for clinical use against IAV infections. In the present study, we tested eight non-receptor tyrosine kinase-inhibitors (NRTKIs) used to treat cancer and autoimmune diseases for their antiviral potential. Six of those potently inhibited virus replication (≥1,000-fold) in A549 cells infected with either A(H1N1)pdm09 or seasonal A(H3N2) strains. These compounds were validated in a biologically relevant ex vivo model of human precision-cut lung slices (hPCLS) to provide proof of principle and show efficacy against contemporary seasonal and pandemic IAVs. We identified the steps of the virus infection cycle affected by these inhibitors and assessed the effect of these NRTKIs on the host response. Considering their established safety profiles, our studies show that the use of these NRTKI shows promise and warrants further development as an alternative strategy to treat influenza virus infections.

show abstract

Section: Discussionmentioning

confidence: 99%

Ex Vivo Validation of Six FDA-Approved Non-Receptor Tyrosine Kinase Inhibitors (NRTKIs) as Antivirals to Pandemic and Seasonal Influenza A Viruses

Meineke

Stelz

Busch

et al. 2022

Preprint

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“…The SFKs regulate cytoskeletal organization, migration, adhesion and proliferation and are implicated in promoting EMT, invasion and metastasis in multiple tumors [55,[158][159][160], including PDAC [161,162]. As mentioned above, multiple autocrine, paracrine, matricrine and yuxtacrine signals stimulate SFK activity [163].…”

Section: Regulation Of Yap By Sfk-mediated Tyrosine Phosphorylationmentioning

confidence: 98%

“…There is increasing interest in elucidating KRAS regulation by direct tyrosine phosphorylation, primarily by members of the structurally related non-receptor Src family of tyrosine kinases (SFKs). The SFK comprises 12 members, (Src, Fyn, Yes, Yrk, Lyn, Hck, Fgr, Blk, Lck, Brk, Srm, and Frk) three of which, Src, Fyn, and Yes, are expressed prominently in many cell types, including human pancreatic cancer cell lines [54], while other members have a more restricted expression pattern, especially to cells of hematopoietic origin [55].…”

Section: Regulation Of Kras Function By Tyrosine Phosphorylation: Contrasting Roles Of Sfk and Shp2mentioning

confidence: 99%

Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance

Eibl

2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, remains a devastating disease. The purpose of this review is to highlight recent literature on mechanistic and translational developments that advance our understanding of a complex crosstalk between KRAS, YAP and Src tyrosine kinase family (SFK) in PDAC development and maintenance. We discuss recent studies indicating the importance of RAS dimerization in signal transduction and new findings showing that the potent pro-oncogenic members of the SFK phosphorylate and inhibit RAS function. These surprising findings imply that RAS may not play a crucial role in maintaining certain subtypes of PDAC. In support of this interpretation, current evidence indicates that the survival of the basal-like subtype of PDAC is less dependent on RAS but relies, at least in part, on the activity of YAP/TAZ. Based on current evidence, we propose that SFK propels PDAC cells to a state of high metastasis, epithelial-mesenchymal transition (EMT) and reduced dependence on KRAS signaling, salient features of the aggressive basal-like/squamous subtype of PDAC. Strategies for PDAC treatment should consider the opposite effects of tyrosine phosphorylation on KRAS and SFK/YAP in the design of drug combinations that target these novel crosstalk mechanisms and overcome drug resistance.

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“…Transformed cells resistant to anoikis can thus generate protrusive tumors, such as the polyps seen in the premalignant stages of colorectal adenocarcinoma. Furthermore, if cells from a growing tumor undergo EMT and basal extrusion, they would eventually cause metastasis (Ortiz et al, 2021;. Adenomatous Polyposis Coli (APC) was indicated as a switch in the decision between apical and basal extrusion.…”

Section: Cell Proliferation Vs Cell Extrusion In Carcinogenesismentioning

confidence: 99%

Cell extrusion in development and cancer, what MARCKS the difference for epithelial integrity?

Veloz¹,

Bosch²,

Aparicio³

et al. 2022

Biocell

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Src family kinases, adaptor proteins and the actin cytoskeleton in epithelial-to-mesenchymal transition

Cited by 85 publications

References 195 publications

Ex Vivo Validation of Six FDA-Approved Non-Receptor Tyrosine Kinase Inhibitors (NRTKIs) as Antivirals to Pandemic and Seasonal Influenza A Viruses

Ex Vivo Validation of Six FDA-Approved Non-Receptor Tyrosine Kinase Inhibitors (NRTKIs) as Antivirals to Pandemic and Seasonal Influenza A Viruses

Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance

Cell extrusion in development and cancer, what MARCKS the difference for epithelial integrity?

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