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The function of the fibrinolytic system was first identified to dissolve fibrin to maintain vascular patency. Connections between the fibrinolytic system and many other physiological and pathological processes have been well established. Dysregulation of the fibrinolytic system is closely associated with multiple pathological conditions, including thrombosis, inflammation, cancer progression, and neuropathies. Thus, molecules in the fibrinolytic system are potent therapeutic and diagnostic targets. This review summarizes the currently used agents targeting this system and the development of novel therapeutic strategies in experimental studies. Future directions for the development of modulators of the fibrinolytic system are also discussed.Fibirinolytic system: an old system as new therapeutic targetsThe fibrinolytic system was originally identified to dissolve blood clots, and is shown to have important roles in other pathological processes, including cancer progression, inflammation, and thrombosis. Molecules or therapeutics targeting fibrinolytic system have been successfully used in the clinical treatments of cancer and thrombotic diseases. The clinical studies and experimental models targeting fibrinolytic system are reviewed by Haili Lin at Sanming First Hosipital, Mingdong Huang at Fuzhou University in China, and Peng Xu at A*STAR in Singapore to demonstrate fibrinolytic system as novel therapeutic targets. As an example, the inhibition of fibrinolytic system protein can be used to suppress cancer prolifieration and metastasis. This review also discusses the potential therapeutic effects of inhibitiors of fibrinolytic system on inflammatory disorders.

Originally identified in Drosophila melanogaster in 1995, the Hippo signaling pathway plays a pivotal role in organ size control and tumor suppression by inhibiting proliferation and promoting apoptosis. Large tumor suppressors 1 and 2 (LATS1/2) directly phosphorylate the Yki orthologs YAP (yes-associated protein) and its paralog TAZ (also known as WW domain-containing transcription regulator 1 [WWTR1]), thereby inhibiting their nuclear localization and pairing with transcriptional coactivators TEAD1-4. Earnest efforts from many research laboratories have established the role of mis-regulated Hippo signaling in tumorigenesis, epithelial mesenchymal transition (EMT), oncogenic stemness, and, more recently, development of drug resistances. Hippo signaling components at the heart of oncogenic adaptations fuel the development of drug resistance in many cancers for targeted therapies including KRAS and EGFR mutants. The first U.S. food and drug administration (US FDA) approval of the imatinib tyrosine kinase inhibitor in 2001 paved the way for nearly 100 small-molecule anti-cancer drugs approved by the US FDA and the national medical products administration (NMPA). However, the low response rate and development of drug resistance have posed a major hurdle to improving the progression-free survival (PFS) and overall survival (OS) of cancer patients. Accumulating evidence has enabled scientists and clinicians to strategize the therapeutic approaches of targeting cancer cells and to navigate the development of drug resistance through the continuous monitoring of tumor evolution and oncogenic adaptations. In this review, we highlight the emerging aspects of Hippo signaling in cross-talk with other oncogenic drivers and how this information can be translated into combination therapy to target a broad range of aggressive tumors and the development of drug resistance.

Reprogramming normal cells into tumour precursors involves complex reconditioning of the tissue microenvironment. Cumulative integration of genetic drivers with extrinsic mechanical inputs is now shown to engage YAP/TAZ to rewire cell mechanics and initiate tumorigenic reprogramming.

In addition to the structural and scaffolding role, the extracellular matrix (ECM) is emerging as a hub for biomechanical signal transduction that is frequently relayed to intracellular sensors to regulate diverse cellular processes. At a macroscopic scale, matrix rigidity confers long-ranging effects contributing towards tissue fibrosis and cancer. The transcriptional co-activators YAP/TAZ, better known as the converging effectors of the Hippo pathway, are widely recognized for their new role as nuclear mechanosensors during organ homeostasis and cancer. Still, how YAP/TAZ senses these “stiffness cues” from the ECM remains enigmatic. Here, we highlight the recent perspectives on the role of agrin in mechanosignaling from the ECM via antagonizing the Hippo pathway to activate YAP/TAZ in the contexts of cancer, neuromuscular junctions, and cardiac regeneration.

An orchestrated wound healing program drives skin repair via collective epidermal cell proliferation and migration. However, the molecular determinants of the tissue microenvironment supporting wound healing remain poorly understood. Herein we discover that proteoglycan Agrin is enriched within the early wound-microenvironment and is indispensable for efficient healing. Agrin enhances the mechanoperception of keratinocytes by augmenting their stiffness, traction stress and fluidic velocity fields in retaliation to bulk substrate rigidity. Importantly, Agrin overhauls cytoskeletal architecture via enhancing actomyosin cables upon sensing geometric stress and force following an injury. Moreover, we identify Matrix Metalloproteinase-12 (MMP12) as a downstream effector of Agrin’s mechanoperception. We also reveal a promising potential of a recombinant Agrin fragment as a bio-additive material that assimilates optimal mechanobiological and pro-angiogenic parameters by engaging MMP12 in accelerated wound healing. Together, we propose that Agrin-MMP12 pathway integrates a broad range of mechanical stimuli to coordinate a competent skin wound healing niche. Replenishing key extracellular matrix (ECM) proteins facilitate wound healing through unclear mechanisms. Here the authors report that injury-triggered Agrin, an ECM proteoglycan, tunes a mechanocompetent niche by engaging MMP-12, thereby enforcing efficient skin wound healing.

Dysregulation of Hippo pathway leads to hyperactivation of YAP-TEAD transcriptional complex in various cancers, including colorectal cancer (CRC). In this study, we observed that HHEX (Hematopoietically expressed homeobox) may enhance transcription activity of the YAP-TEAD complex. HHEX associates with and stabilizes the YAP-TEAD complex on the regulatory genomic loci to coregulate the expression of a group of YAP/TEAD target genes. Also, HHEX may indirectly regulate these target genes by controlling YAP/TAZ expression. Importantly, HHEX is required for the pro-tumorigenic effects of YAP during CRC progression. In response to serum stimulation, CK2 (Casein Kinase 2) phosphorylates HHEX and enhances its interaction with TEAD4. A CK2 inhibitor CX-4945 diminishes the interaction between HHEX and TEAD4, leading to decreased expression of YAP/TEAD target genes. CX-4945 synergizes the antitumor activity of YAP-TEAD inhibitors verteporfin and Super-TDU. Elevated expression of HHEX is correlated with hyperactivation of YAP/TEAD and associated with poor prognosis of CRC patients. Overall, our study identifies HHEX as a positive modulator of YAP/TEAD to promote colorectal tumorigenesis, providing a new therapeutic strategy for targeting YAP/TEAD in CRC. Hippo signalling is often deregulated in cancers. Here the authors show that CK2 enhances the cooperation of HHEX with YAP-TEAD complex to promote colorectal tumorigenesis.

The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Latsl/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4DcAF1. Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Latsl/2-binding site on the Merlin FERM domain is physically blocked by Merlin＇s auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin＇s binding to Latsl/2. Phosphorylation of Ser518 outside the Merlin＇s auto-inhibitory tail does not obviously alter Merlin＇s conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin- binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.

The transcriptional coactivators TAZ and YAP pair with transcriptional enhanced associate domains (TEADs) to regulate transcription. TAZ and YAP nuclear condensates ensure optimal transcription. A new study reports that FUS regulates TAZ condensates by maintaining them in a fluid state to drive transcription of target genes.

Rab proteins play crucial roles in membrane trafficking. Some Rab proteins are implicated in cancer development through regulating protein sorting or degradation. In this study, we found that the expression of Rab26 is suppressed in the aggressive breast cancer cells as compared to the levels in non-invasive breast cancer cells. Over-expression of Rab26 inhibits cell migration and invasion, while Rab26 knockdown significantly promotes the migration and invasion of breast cancer cells. Rab26 reduces focal adhesion association of Src kinase and induces endosomal translocation of Src. Further experiments revealed that Rab26 mediates the autophagic degradation of phosphorylated Src through interacting with ATG16L1, consequently, resulting in the suppression of the migration and invasion ability of breast cancer cells.

The Hippo pathway is a tumor suppressor pathway that is implicated in the regulation of organ size. The pathway has three components: the upstream regulatory factors, the kinase core, and the downstream transcriptional machinery, which consists of YAP, TAZ (transcription co-activators) and TEAD (transcription factor). Formation of YAP/TAZ-TEAD complexes leads to the transcription of growth-promoting genes. Herein, we report the crystal structure of TAZ-TEAD4 complex, which reveals two binding modes. The first is similar to the published YAP-TEAD structure. The second is a unique binding mode, whereby two molecules of TAZ bind to and bridge two molecules of TEAD4. We validated the latter using cross-linking and multi-angle light scattering. Using siRNA, we showed that TAZ knockdown leads to a decrease in TEAD4 dimerization. Lastly, results from luciferase assays, using YAP/TAZ transfected or knockdown cells, give support to the non-redundancy of YAP/TAZ co-activators in regulating gene expression in the Hippo pathway.