Journal ArticleDOI
Signal transduction by focal adhesion kinase in cancer
Jihe Zhao,Jun-Lin Guan +1 more
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TLDR
The intensive research on FAK signaling in cancer have yielded a wealth of information on this pivotal kinase and these and future studies are leading to potentially novel therapies for cancer.Abstract:
Cellular interactions with extracellular matrix play essential roles in tumor initiation, progression and metastasis. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase identified as a key mediator of signaling by integrins, a major family of cell surface receptors for extracellular matrix, as well as other receptors in both normal and cancer cells. FAK is activated by integrins through disruption of an auto-inhibitory intra-molecular interaction between its kinase domain and the amino terminal FERM domain. The activated FAK forms a binary complex with Src family kinases which can phosphorylate other substrates and trigger multiple intracellular signaling pathways to regulate various cellular functions. Subcellular localization of FAK in focal adhesions is essential for FAK signaling, which is another distinguishing feature of the kinase. Integrin-FAK signaling has been shown to activate a number of signaling pathways through phosphorylation and protein-protein interactions to promote tumorigenesis. FAK also plays a prominent role in tumor progression and metastasis through its regulation of both cancer cells and their microenvironments including cancer cell migration, invasion, epithelial to mesenchymal transition, and angiogenesis. More recently, a role for FAK in tumor initiation and progression has been demonstrated directly using xenograft as well as conditional knockout mouse models. In agreement with these experimental data, overexpression and activation of FAK have been found in a variety of human cancers. A number of small molecule inhibitors for FAK have been developed and in various phases of testing for cancer treatments. Overall, the intensive research on FAK signaling in cancer have yielded a wealth of information on this pivotal kinase and these and future studies are leading to potentially novel therapies for cancer.read more
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Journal ArticleDOI
FAK in cancer: mechanistic findings and clinical applications
TL;DR: Focal adhesion kinase signalling effects on both tumour and stromal cell biology that provide rationale and support for future therapeutic opportunities are discussed.
Journal ArticleDOI
Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis
Xiaofeng Zhao,Jun-Lin Guan +1 more
TL;DR: Small molecular inhibitors for FAK kinase activity as well as future development of novel therapies targeting the potentially kinase-independent functions of FAK are promising treatments for metastatic cancer aswell as other diseases.
Journal ArticleDOI
Actomyosin-Mediated Cellular Tension Drives Increased Tissue Stiffness and β-Catenin Activation to Induce Epidermal Hyperplasia and Tumor Growth
Michael S. Samuel,Jose Lopez,Ewan J. McGhee,Daniel R. Croft,David Strachan,Paul Timpson,June Munro,Ewald Schroder,Jing Zhou,Valerie G. Brunton,Nick Barker,Hans Clevers,Owen J. Sansom,Kurt I. Anderson,Valerie M. Weaver,Michael F. Olson +15 more
TL;DR: Tumor number, growth, and progression were increased by ROCK activation, while ROCK blockade was inhibitory, implicating actomyosin-mediated cellular tension and consequent collagen deposition as significant tumor promoters.
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Mechanisms of motility in metastasizing cells.
TL;DR: In most epithelial cancers, loss of the cell-cell adhesion molecule E-cadherin and gain of mesenchymal markers and promigratory signals underlie the conversion of epithelial, differentiated cells to meschymal, migratory, and invasive cells, a process referred to as the epithelial-to-mesenchymAl transition.
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Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance.
TL;DR: Multiple levels of cross-talk between the PI3K (phosphoinositide 3-kinase)/Akt and Ras/MAPK (mitogen-activated protein kinase) signalling pathways are described.
References
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Journal ArticleDOI
Integrins: Bidirectional, Allosteric Signaling Machines
TL;DR: Current structural and cell biological data suggest models for how integrins transmit signals between their extracellular ligand binding adhesion sites and their cytoplasmic domains, which link to the cytoskeleton and to signal transduction pathways.
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Complex networks orchestrate epithelial–mesenchymal transitions
TL;DR: Understanding how mesenchymal cells arise from an epithelial default status will also have a strong impact in unravelling the mechanisms that control fibrosis and cancer progression.
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Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels
Peter C. Brooks,Anthony M.P. Montgomery,Mauricio Rosenfeld,Ralph A. Reisfeld,Tianhua Hu,George Klier,David A. Cheresh +6 more
TL;DR: In this article, a single intravascular injection of a cyclic peptide or monoclonal antibody antagonist of integrin alpha v beta 3 disrupts ongoing angiogenesis on the chick chorioallantoic membrane (CAM).
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Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery
TL;DR: Recent studies indicate that numerous components of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway are targeted by amplification, mutation and translocation more frequently than any other pathway in cancer patients, with resultant activation of the pathway.
Journal ArticleDOI
Generation of a functional mammary gland from a single stem cell
Mark Shackleton,Mark Shackleton,François Vaillant,François Vaillant,Kaylene J. Simpson,Kaylene J. Simpson,John Stingl,Gordon K. Smyth,Marie Liesse Asselin-Labat,Marie Liesse Asselin-Labat,Li Wu,Geoffrey J. Lindeman,Geoffrey J. Lindeman,Jane E. Visvader,Jane E. Visvader +14 more
TL;DR: It is shown that a single cell, marked with a LacZ transgene, can reconstitute a complete mammary gland in vivo and establish that single cells within the Lin-CD29hiCD24+ population are multipotent and self-renewing, properties that define them as MaSCs.