Role of the ABL tyrosine kinases in the epithelial-mesenchymal transition and the metastatic cascade.
Ontology highlight
ABSTRACT:
SUBMITTER: Luttman JH
PROVIDER: S-EPMC8140471 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Metastasis is the end stage of cancer progression and the direct cause of most cancer-related deaths. The spreading of cancer cells from the primary site to distant organs is a multistep process known as the metastatic cascade, including local invasion, intravasation, survival in the circulation, extravasation, and colonization. Each of these steps is driven by the acquisition of genetic and/or epigenetic alterations within cancer cells, leading to subsequent transformation of metastatic cells. Epithelial-mesenchymal transition (EMT), a cellular process mediating the conversion of cell from epithelial to mesenchymal phenotype, and its reverse transformation, termed mesenchymal-epithelial transition (MET), together endow metastatic cells with traits needed to generate overt metastases in different scenarios. The dynamic shift between these two phenotypes and their transitional state, termed partial EMT, emphasizes the plasticity of EMT. Recent advances attributed this plasticity to epigenetic regulation, which has implications for the therapeutic targeting of cancer metastasis. In this review, we will discuss the association between epigenetic events and the multifaceted nature of EMT, which may provide insights into the steps of the cancer metastatic cascade.
| S-EPMC8117142 | biostudies-literature
Project description:Previously, we showed that Abl kinases (c-Abl, Arg) are activated downstream of PDGF in a manner dependent on Src kinases and PLC-gamma1, and promote PDGF-mediated proliferation and migration of fibroblasts. We additionally demonstrated that Abl kinases bind directly to PDGFR-beta via their SH2 domains.In this study, we extend these findings by demonstrating that Abl kinases also are activated downstream of aPDGF autocrine growth loop in glioblastoma cells, indicating that the PDGFR-Abl signaling pathway also is likely to be important in glioblastoma development and/or progression.We recently showed that Abl kinases are highly active in many breast cancer cell lines, and the Her-2 receptor tyrosine kinase contributes to c-Abl and Arg kinase activation. In this study, we show that Abl kinase SH2 domains bind directly to Her-2, and like PDGFR-beta , Her-2 directly phosphorylates c-Abl. Previously, we demonstrated that PDGFR-beta directly phosphorylates Abl kinases in vitro, and Abl kinases reciprocally phosphorylate PDGFR-beta . Here, we show that PDGFR-beta-phosphorylation of Abl kinases has functional consequences as PDGFR-beta phosphorylates Abl kinases on Y245 and Y412, sites known to be required for activation of Abl kinases. Moreover, PDGFR-beta phosphorylates Arg on two additional unique sites whose function is unknown. Importantly, we also show that Abl-dependent phosphorylation of PDGFR-beta has functional and biological significances. c-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis. These data are exciting as they indicate that Abl kinases not only are activated by PDGFR and promote PDGFR-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off PDGFR-mediated chemotaxis.
| S-EPMC2701649 | biostudies-literature
Project description:Protein tyrosine kinases are crucial to cellular signaling pathways regulating cell growth, proliferation, metabolism, differentiation, and migration. To maintain normal regulation of cellular signal transductions, the activities of tyrosine kinases are also highly regulated. The conformation of a three-residue motif Asp-Phe-Gly (DFG) near the N-terminus of the long "activation" loop covering the catalytic site is known to have a critical impact on the activity of c-Abl and c-Src tyrosine kinases. A conformational transition of the DFG motif can switch the enzyme from an active (DFG-in) to an inactive (DFG-out) state. In the present study, the string method with swarms-of-trajectories was used to computationally determine the reaction pathway connecting the two end-states, and umbrella sampling calculations were carried out to characterize the thermodynamic factors affecting the conformations of the DFG motif in c-Abl and c-Src kinases. According to the calculated free energy landscapes, the DFG-out conformation is clearly more favorable in the case of c-Abl than that of c-Src. The calculations also show that the protonation state of the aspartate residue in the DFG motif strongly affects the in/out conformational transition in c-Abl, although it has a much smaller impact in the case of c-Src due to local structural differences.
| S-EPMC4315421 | biostudies-literature
Project description:Adherens junctions are calcium-dependent cell-cell contacts that link neighboring cells through cadherin receptors. Coordinated regulation of the actin cytoskeleton by the Rho GTPases is required for the formation and dissolution of adherens junctions. However, the pathways that link cadherin signaling to cytoskeletal regulation remain poorly defined. Here we identify the Abl family kinases as critical mediators of cadherin-mediated adhesion. Endogenous Abl family kinases, Abl and Arg, are activated and required for Rac activation after cadherin engagement and regulate the formation and maintenance of adherens junctions in mammalian cells. Significantly, we show that Abl-dependent regulation of the Rho-ROCK-myosin signaling pathway is critical for the maintenance of adherens junctions. Inhibition of the Abl kinases in epithelial sheets results in the activation of Rho and its downstream target ROCK, leading to enhanced phosphorylation of the myosin regulatory light chain. These signaling events result in enhanced stress fiber formation and increased actomyosin contractility, thereby disrupting adherens junctions. Conversely, Arg gain of function promotes adherens junction formation through a Crk-dependent pathway in cells with weak junctions. These data identify the Abl kinases as a regulatory link between the cadherin-catenin adhesion complex and the actin cytoskeleton through regulation of Rac and Rho during adherens junction formation, and also reveal a functional link between Abl and Rho that is essential for adherens junction stability.
| S-EPMC2077043 | biostudies-literature
Project description:Medulloblastoma is the most common malignant pediatric brain tumor, and leptomeningeal dissemination (LMD) of medulloblastoma portends a poorer prognosis at diagnosis and is incurable at recurrence. The biological mechanisms underlying LMD in medulloblastoma are largely unclear. The Abelson (ABL) family of non-receptor tyrosine kinases has been implicated in cancer cell migration, invasion, adhesion, and chemotherapy resistance, and these kinases are upstream mediators of the oncogene c-MYC in fibroblasts. However, their role in medulloblastoma has not yet been explored. Therefore, the purpose of this work is to elucidate the role of the ABL kinases, ABL1 and ABL2, in medulloblastoma LMD. We show here that ABL1/2 mRNA is highly expressed in human medulloblastoma tumor samples and cell lines and that pharmacologic inhibition of ABL kinases results in medulloblastoma cell death. Knockdown of the ABL kinase genes ABL1 and ABL2 results in decreased adhesion to the extracellular matrix protein, vitronectin, and decreased medulloblastoma proliferation in a mouse model of medulloblastoma LMD (resulting in decreased tumor burden with subsequent increased overall survival. Further, both pharmacologic inhibition of ABL1/2 and ABL1/2 knockdown resulted in decreased c-myc expression, revealing a putative signaling pathway. In summary, this work highlights the potential role of ABL kinases in medulloblastoma LMD via c-myc expression.
2023-10-04 | GSE224691 | GEO
Project description:Although members of the p63 family of transcription factors are known for their role in the development and differentiation of epithelial surfaces, their function in cancer is less clear. Here, we show that depletion of the ?Np63? and ? isoforms, leaving only ?Np63?, results in epithelial to mesenchymal transition (EMT) in the normal breast cell line MCF10A. EMT can be rescued by the expression of the ?Np63? isoform. We also show that ?Np63? expressed in a background where all the other ?Np63 are knocked down causes EMT with an increase in TGF?-1, -2, and -3 and downstream effectors Smads2/3/4. In addition, a p63 binding site in intron 1 of TGF? was identified. Inhibition of the TGF? response with a specific inhibitor results in reversion of EMT in ?Np63?- and ?-depleted cells. In summary, we show that p63 is involved in inhibiting EMT and reduction of certain p63 isoforms may be important in the development of epithelial cancers.
| S-EPMC3030392 | biostudies-literature
Project description:Over a century of scientific inquiry since the discovery of v-SRC but still no final judgement on SRC function. However, a significant body of work has defined Src family kinases as key players in tumor progression, invasion and metastasis in human cancer. With the ever-growing evidence supporting the role of epithelial-mesenchymal transition (EMT) in invasion and metastasis, so does our understanding of the role SFKs play in mediating these processes. Here we describe some key mechanisms through which Src family kinases play critical role in epithelial homeostasis and how their function is essential for the propagation of invasive signals. Video abstract.
| S-EPMC8247114 | biostudies-literature
Project description:Epithelial-mesenchymal transition (EMT) plays a fundamental role in cancer metastasis. The ubiquitin ligase FBXW7, a general tumor suppressor in human cancer, has been implicated in diverse cellular processes, however, its role in cholangiocarcinoma (CCA) metastasis has not been identified. Here, we report a crucial role of FBXW7 in CCA metastasis by regulating EMT. Loss of FBXW7 expression was detected in CCA cells and clinical specimens. Clinicopathological analysis revealed a close correlation between FBXW7 deficiency and metastasis, TNM stage and differentiation in intrahepatic CCA and perihilar CCA. Moreover, FBXW7 silencing in CCA cells dramatically promoted EMT, stem-like capacity and metastasis both in vitro and in vivo. Conversely, FBXW7 overexpression attenuated these processes. Mechanistically, treatment with rapamycin, a mTOR inhibitor, inhibited EMT, stem-like capacity and metastasis induced by FBXW7 silencing both in vitro and in vivo. Furthermore, the expression of EMT regulating transcription factors, snail, slug and ZEB1, were also decreased markedly with rapamycin treatment. In addition, silencing ZEB1 inhibited EMT and metastasis of both CCA cells and FBXW7 deficient CCA cells, which implicated the potential role of ZEB1 in FBXW7/mTOR signaling pathway related CCA metastasis. In conclusion, our findings defined a pivotal function of FBXW7 in CCA metastasis by regulating EMT.
| S-EPMC4467439 | biostudies-literature
Project description:[This corrects the article DOI: 10.1371/journal.pone.0119954.].
| S-EPMC4500445 | biostudies-literature
Project description:Epithelial-mesenchymal transition (EMT), crucial during embryogenesis for new tissue and organ formation, is also considered to be a prerequisite to cancer metastasis. We report here that the protein tyrosine phosphatase Pez is expressed transiently in discrete locations in developing brain, heart, pharyngeal arches, and somites in zebrafish embryos. We also find that Pez knock-down results in defects in these organs, indicating a crucial role in organogenesis. Overexpression of Pez in epithelial MDCK cells causes EMT, with a drastic change in cell morphology and function that is accompanied by changes in gene expression typical of EMT. Transfection of Pez induced TGFbeta signaling, critical in developmental EMT with a likely role also in oncogenic EMT. In zebrafish, TGFbeta3 is co- expressed with Pez in a number of tissues and its expression was lost from these tissues when Pez expression was knocked down. Together, our data suggest Pez plays a crucial role in organogenesis by inducing TGFbeta and EMT.
| S-EPMC2064655 | biostudies-literature