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Matsui H.,Tohoku University | Matsui H.,Locomotive Syndrome Research Institute | Fukuno N.,Tohoku University | Kanda Y.,Tohoku University | And 12 more authors.
Journal of Biological Chemistry

Background: Fn14 is a highly inducible member of the TNF receptor family. Results: Large-magnitude mechanical stress induced Fn14 expression via JNK in osteoblasts. Conclusion: Expression of Fn14 regulates mechanical stress-induced apoptosis in osteoblasts. Significance: This is the first elucidation of the mechanism of excessive mechanical stress-induced apoptosis mediated by Fn14. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Machiyama H.,National University of Singapore | Machiyama H.,Osaka University | Hirata H.,National University of Singapore | Loh X.K.,National University of Singapore | And 6 more authors.
Journal of Cell Science

Cell adhesion complexes provide platforms where cell-generated forces are transmitted to the extracellular matrix (ECM). Tyrosine phosphorylation of focal adhesion proteins is crucial for cells to communicate with the extracellular environment. However, the mechanisms that transmit actin cytoskeletal motion to the extracellular environment to drive cell migration are poorly understood. We find that the movement of p130Cas (Cas, also known as BCAR1), a mechanosensor at focal adhesions, correlates with actin retrograde flow and depends upon actomyosin contraction and phosphorylation of the Cas substrate domain (CasSD). This indicates that CasSD phosphorylation underpins the physical link between Cas and the actin cytoskeleton. Fluorescence recovery after photobleaching (FRAP) experiments reveal that CasSD phosphorylation, as opposed to the association of Cas with Src, facilitates Cas displacement from adhesion complexes in migrating cells. Furthermore, the stabilization of Src-Cas binding and inhibition of myosin II, both of which sustain CasSD phosphorylation but mitigate Cas displacement from adhesion sites, retard cell migration. These results indicate that Cas promotes cell migration by linking actomyosin contractions to the adhesion complexes through a dynamic interaction with Src as well as through the phosphorylation-dependent association with the actin cytoskeleton. © 2014. Published by The Company of Biologists Ltd. Source

Zhao Z.,National University of Singapore | Tan S.H.,National University of Singapore | Machiyama H.,National University of Singapore | Kawauchi K.,National University of Singapore | And 6 more authors.
Biology Open

Cell migration is a highly dynamic process that plays pivotal roles in both physiological and pathological processes. We have previously reported that p130Cas supports cell migration through the binding to Src as well as phosphorylation-dependent association with actin retrograde flow at focal adhesions. However, it remains elusive how phosphorylated Cas interacts with actin cytoskeletons. We observe that the actin-binding protein, tensin 1, co-localizes with Cas, but not with its phosphorylation-defective mutant, at focal adhesions in leading regions of migrating cells. While a truncation mutant of tensin 1 that lacks the phosphotyrosine-binding PTB and SH2 domains (tensin 1-SH2PTB) poorly co-localizes or co-immunoprecitates with Cas, bacterially expressed recombinant tensin 1-SH2PTB protein binds to Cas in vitro in a Cas phosphorylation-dependent manner. Furthermore, exogenous expression of tensin 1-SH2PTB, which is devoid of the actin-interacting motifs, interferes with the Cas-driven cell migration, slows down the inward flux of Cas molecules, and impedes the displacement of Cas molecules from focal adhesions. Taken together, our results show that tensin 1 links inwardly moving actin cytoskeletons to phosphorylated Cas at focal adhesions, thereby driving cell migration. © 2016. Published by The Company of Biologists Ltd |. Source

Osteoarthritis (OA) is a disease caused by the degeneration and destruction of joint cartilage followed by peri-articular or subchondral bone formation and concomitant degeneration of other components of joints including synovium. Several animal OA models that adopt surgically induced joint instability have been developed. Analysis of those OA models indicates that increased mechanical stress exacerbates OA. In contrast, the effectiveness of physical therapy to alleviate OA symptoms suggests that optimal mechanical stimulation can impede the progression of OA. We propose that there are two facets of mechanical stress in light of the influence on OA ; one is detrimental, whilst the other is beneficial for articular cartilage and other joint compositions. From the malalignment and incongruity that underlie hip OA succeeding to congenital hip dislocation (acetabular hypoplasia) and the varus (or valgus) deformity observed in knee OA, shear force appears to prone to be a villain mechanical stress. On the other hand, compressive force may facilitate the maintenance or turnover of the articular cartilage unless it becomes excessive. Although essential differences between detrimental and beneficial mechanical stresses remain elusive, we speculate that the degree or magnitude of the deformation of mechano-sensor(s) may be crucial. Uncovering the mechano-sensing machinery in joints may demarcate the beneficial mechanical stress, and bring about a paradigm shift in the therapeutic strategy for OA. Source

Matsui H.,Locomotive Syndrome Research Institute | Harada I.,Locomotive Syndrome Research Institute | Sawada Y.,Locomotive Syndrome Research Institute | Sawada Y.,National University of Singapore
Genes and Cancer

Anchorage-independent growth is the most significant hallmark of cell transformation, which has an intimate relevance to cancer. Anchorage or adhesion physically links cells to the extracellular matrix and allows the transmission of external mechanical cues to intracellular signaling machineries. Transformation involves acquiring the ability to proliferate without requiring mechanically initiated signal transduction, known as mechanotransduction. A number of signaling and cytoskeletal molecules are located at focal adhesions. Src and its related proteins, including p130Cas, localize to adhesion sites, where their functions can be mechanically regulated. In addition, the aberrant activation and expression of Src and p130Cas are linked to transformation and malignancy both in vitro and in vivo. These findings shed light on the importance of mechanotransduction in tumorigenesis and the regulation of cancer progression and also provide insights into the mechanical aspects of cancer signaling. © The Author(s) 2012. Source

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