Rho-GEF Trio regulates osteosarcoma progression and osteogenic differentiation through Rac1 and RhoA

Osteosarcoma (OS) is the most common primary bone tumor. Its high mortality rate and metastasis rate seriously threaten human health. Currently, the treatment has reached a plateau, hence we urgently need to explore new therapeutic directions. In this paper, we found that Trio was highly expressed in osteosarcoma than normal tissues and promoted the proliferation, migration, and invasion of osteosarcoma cells. Furthermore, Trio inhibited osteosarcoma cells’ osteogenic differentiation in vitro and accelerated the growth of osteosarcoma in vivo. Given Trio contains two GEF domains, which have been reported as the regulators of RhoGTPases, we further discovered that Trio could regulate osteosarcoma progression and osteogenic differentiation through activating RhoGTPases. In summary, all our preliminary results showed that Trio could be a potential target and prognostic marker of osteosarcoma.

Interphase microtubule disassembly is a signaling cue that drives cell rounding at mitotic entry.

Reorganization of the cortical actin cytoskeleton at mitotic entry is essential to increase membrane tension for cell rounding. This spherical shape is necessary for the biogenesis and organization of the mitotic spindle. Proteins of the Ezrin, Radixin, Moesin (ERM) family play essential roles in mitotic morphogenesis by linking actomyosin forces to the plasma membrane. While ERMs drive metaphase cell rounding, the cell-cycle signals that prompt their conformational activation in mitosis are unknown. We screened a library of small molecules using novel ERM biosensors and we unexpectedly found that drugs that disassemble microtubules promote ERM activation. Remarkably, cells disassemble their interphase microtubules while entering mitosis. We further discovered that this disassembly of microtubules acts as a cell-cycle signal that directs ERM activation and metaphase cell rounding. We show that GEF-H1, a Rho-GEF inhibited by microtubule binding, acts downstream of microtubule disassembly to activate ERMs via RhoA and its kinase effector SLK. In addition, we demonstrate that GEF-H1 and Ect2, another Rho-GEF responsible for the generation of mitotic actomyosin forces, act together to drive metaphase ERM activation and cell rounding. In summary, we report microtubule disassembly as a cell cycle signal that triggers a signaling network ensuring that actomyosin forces are efficiently integrated at the plasma membrane to promote cell rounding at mitotic entry.

A mathematical analysis of an activator-inhibitor Rho GTPase model

<p style='text-indent:20px;'>Recent experimental observations reveal that local cellular contraction pulses emerge via a combination of fast positive and slow negative feedbacks based on a signal network composed of Rho, GEF and Myosin interactions [<xref ref-type="bibr" rid="b22">22</xref>]. As an examplary, we propose to study a plausible, hypothetical temporal model that mirrors general principles of fast positive and slow negative feedback, a hallmark for activator-inhibitor models. The methodology involves (ⅰ) a qualitative analysis to unravel system switching between different states (stable, excitable, oscillatory and bistable) through model parameter variations; (ⅱ) a numerical bifurcation analysis using the positive feedback mediator concentration as a bifurcation parameter, (ⅲ) a sensitivity analysis to quantify the effect of parameter uncertainty on the model output for different dynamic regimes of the model system; and (ⅳ) numerical simulations of the model system for model predictions. Our methodological approach supports the role of mathematical and computational models in unravelling mechanisms for molecular and developmental processes and provides tools for analysis of temporal models of this nature.</p>

The Rho-GEF PIX-1 directs assembly or stability of lateral attachment structures between muscle cells

PIX proteins are guanine nucleotide exchange factors (GEFs) that activate Rac and Cdc42, and are known to have numerous functions in various cell types. Here, we show that a PIX protein has an important function in muscle. From a genetic screen in C. elegans, we found that pix-1 is required for the assembly of integrin adhesion complexes (IACs) at borders between muscle cells, and is required for locomotion of the animal. A pix-1 null mutant has a reduced level of activated Rac in muscle. PIX-1 localizes to IACs at muscle cell boundaries, M-lines and dense bodies. Mutations in genes encoding proteins at known steps of the PIX signaling pathway show defects at muscle cell boundaries. A missense mutation in a highly conserved residue in the RacGEF domain results in normal levels of PIX-1 protein, but a reduced level of activated Rac in muscle, and abnormal IACs at muscle cell boundaries.

Patents targeting the Warburg effect for cancer therapy: an interview with William P Katt

Dr William Katt is a multidisciplinary scientist with particular focus in computational, synthetic and biological chemistry. He obtained his undergraduate degree at Rensselaer Polytechnic Institute and performed his graduate studies at Yale University, where he focused on designing small-molecule inhibitors of the Rho/Rho GEF interaction. Following those studies, Dr Katt accepted a fellowship from the American Cancer Society which funded his work at Cornell University, where he investigated small-molecule inhibitors of the enzyme glutaminase, a key player in cancer metabolism. Today, Dr Katt is a research associate at Cornell and maintains a number of collaborations with researchers across the nation examining glutaminase, cancer stem cells, nano-therapeutics and more, with the goal of developing therapeutic approaches that will eventually help patients in the clinic.