MOB kinase activator 1A acts as an oncogene by targeting PI3K/AKT/mTOR in ovarian cancer.

BACKGROUND: To illuminate the precise roles of MOB Kinase Activator 1 A (MOB1A) in the development of ovarian cancer (OC). METHODS: MOB1A expression and clinical data of OC were obtained from the public database on gene expression and proteomics. Meanwhile, verification of expression was carried out in Gene Expression Omnibus, the Human Protein Atlas, and OC cell lines. The prognosis of MOB1A was explored in the Kaplan-Meier plotter. RNA interference and lentivirus vectors were applied to construct knockdown and overexpressed cell models. Changes in the malignant behaviors of OC cells were detected by cholecystokinin octopeptide cell counting kit, wound healing, colony formation assay, transwell, flow cytometry assays, and in vivo experiments. Changes in proteins in the PI3K and autophagy-related makers were detected by western blot analysis. RESULTS: The expression of MOB1A was significantly upregulated and accompanied by an inferior survival rate in OC. Knockdown of MOB1A inhibited the proliferation, invasion, migration, and cell cycle of OC cells, whereas induced cell autophagy. MOB1A upregulation had the opposite effects. In addition, bioinformatics analysis and western blot experiments showed that MOB1A plays an important role in the PI3K/AKT/mTOR pathway. CONCLUSIONS: Our findings indicated that MOB1A is highly expressed and related to poor prognosis in OC. MOB1A plays a role in promoting the malignant biological behavior of tumor cells through PI3K/AKT/mTOR signaling pathway.

miR-548ag functions as an oncogene by suppressing MOB1B in the development of obesity-related endometrial cancer.

Obesity is a high-risk factor in the development of endometrial cancer (EC). Our previous study observed that miR-548ag was significantly overexpressed in the sera of obese individuals. Here, we report the function of miR-548ag and its mechanism in promoting the obesity-related progression of EC. The content of miR-548ag was increased in the serum of obese EC individuals. Bioinformatics analysis indicated that the survival rate of EC patients with a higher expression of miR-548ag was significantly reduced. The Mps One Binder Kinase Activator 1B (MOB1B, the core member of the Hippo signaling pathway) is a direct target gene of miR-548ag, which is inversely correlated with the expression of miR-548ag. The overexpression of miR-548ag enhances the proliferation, invasion, and migration, and inhibits apoptosis by downregulating the expression of MOB1B, leading to the deactivation of the Hippo pathway in EC cell lines and contributing to tumor progression in vivo. Our study has established that miR-548ag functions as an oncogene by suppressing MOB1B in the development of obesity-related EC.

Tubuloside B, isolated from Cistanche tubulosa, a promising agent against M1 macrophage activation via synergistically targeting Mob1 and ERK1/2.

Targeting macrophage M1 polarization is a promising strategy with fewer detrimental effects in COVID-19 curation. Phenylethanoid glycosides (PhGs) of Cistanche tubulosa are a botanical drug to possess various anti-inflammation-related functions, such as immunomodulating, hepatoprotective or neuroprotective functions, whereas their anti-inflammatory activity is rarely understood. A search into their anti-inflammatory characteristics led to the isolation of 49 PhGs along with 15 new PhGs. Their inhibitory effects against M1 polarization induced by LPS plus IFN-γ were explored in RAW264.7 macrophages. Of these PhGs, tubuloside B (Tub B) exerted substantial NO scavenging effect both in chemical- and cell-based assays, and it inhibited massive production of cytokines and chemokines. Tub B decreased ERK1/2 phosphorylation via direct binding and inhibited the MAPK signaling pathway. Tub B also directly binded to Mob1 protein, thereby increased the stability and level of Mob1 protein by inhibiting ubiquitinated degradation. Mob1 was pivotal for the anti-inflammatory activity of Tub B, and it acted independently of the canonical Hippo-YAP pathway. Moreover, ERK1/2 and Mob1 also had a synergic effect on modulating the inflammatory response. Finally, these effects of Tub B were verified in mice with LPS-induced systemic inflammatory response syndrome. Taken together, these results indicated that Tub B acted as a promising agent against M1 macrophage activation by synergistically targeting ERK1/2 and Mob1, and that it may potentially be a drug candidate to prevent/treat inflammatory diseases, especially in COVID-19.

Hippo-TAZ signaling is the master regulator of the onset of triple-negative basal-like breast cancers.

Breast cancer is the most frequent malignancy in women worldwide. Basal-like breast cancer (BLBC) is the most aggressive form of this disease, and patients have a poor prognosis. Here, we present data suggesting that the Hippo-transcriptional coactivator with PDZ-binding motif (TAZ) pathway is a key driver of BLBC onset and progression. Deletion of Mob1a/b in mouse mammary luminal epithelium induced rapid and highly reproducible mammary tumorigenesis that was dependent on TAZ but not yes-associated protein 1 (YAP1). In situ early-stage BLBC-like malignancies developed in mutant animals by 2 wk of age, and invasive BLBC appeared by 4 wk. In a human estrogen receptor+ luminal breast cancer cell line, TAZ hyperactivation skewed the features of these luminal cells to the basal phenotype, consistent with the aberrant TAZ activation frequently observed in human precancerous BLBC lesions. TP53 mutation is rare in human precancerous BLBC but frequent in invasive BLBC. Addition of Trp53 deficiency to our Mob1a/b-deficient mouse model enhanced tumor grade and accelerated cancer progression. Our work justifies targeting the Hippo-TAZ pathway as a therapy for human BLBC, and our mouse model represents a powerful tool for evaluating candidate agents.

MiR-743a-5p regulates differentiation of myoblast by targeting Mob1b in skeletal muscle development and regeneration.

The microRNAs (miRNAs) play an important role in regulating myogenesis by targeting mRNA. However, the understanding of miRNAs in skeletal muscle development and diseases is unclear. In this study, we firstly performed the transcriptome profiling in differentiating C2C12 myoblast cells. Totally, we identified 187 miRNAs and 4260 mRNAs significantly differentially expressed that were involved in myoblast differentiation. We carried out validation of microarray data based on 5 mRNAs and 5 miRNAs differentially expressed and got a consistent result. Then we constructed and validated the significantly up- and down-regulated mRNA-miRNA interaction networks. Four interaction pairs (miR-145a-5p-Fscn1, miR-200c-5p-Tmigd1, miR-27a-5p-Sln and miR-743a-5p-Mob1b) with targeted relationships in differentiated myoblast cells were demonstrated. They are all closely related to myoblast development. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated cell cycle signals important for exploring skeletal muscle development and disease. Functionally, we discovered that miR-743a targeting gene Mps One Binder Kinase Activator-Like 1B (Mob1b) gene in differentiated C2C12. The up-regulated miR-743a can promote the differentiation of C2C12 myoblast. While the down-regulated Mob1b plays a negative role in differentiation. In addition, the expression profile of miR-743a and Mob1b are consistent with skeletal muscle recovery after Cardiotoxin (CTX) injury. Our study revealed that miR-743a-5p regulates myoblast differentiation by targeting Mob1b involved in skeletal muscle development and regeneration. Our findings made a further exploration for mechanisms in myogenesis and might provide potential possible miRNA-based target therapies for skeletal muscle regeneration and disease in the near future.

Up-regulation of MTHFD2 is associated with clinicopathological characteristics and poor survival in ovarian cancer, possibly by regulating MOB1A signaling.

BACKGROUND: MTHFD2 is a folate-coupled metabolic enzyme, which has been proved to participant in the metabolic reprogramming and tumor cell-sustaining proliferative capacity. However, the function of MTHFD2 in the development of ovarian cancer and its potential molecular mechanisms is still unclear. MATERIALS AND METHODS: The expression, various mutations, prognosis, and related network signaling pathways of MTHFD2 were analyzed using bioinformatics-related websites, including Oncomine, GEPIA, UCSC, cBioPortal, KM Plotter, TISIDB and TIMER. The prognostic value of MTHFD2 expression was validated by our own ovarian cancer samples using RT-qPCR. The migration ad invasion of ovarian cancer cells were further analyzed by CCK-8 and transwell assay. The Western-blot assay was performed to explore the protein levels of MTHFD2 and MOB1A. RESULTS: We obtained the following important results. (1) MTHFD2 expression was markedly up-regulated in ovarian cancer than normal samples. (2) Among patients with ovarian cancer, those with higher MTHFD2 expression was associated with lower survival rate. (3) The major mutation type of MTHFD2 in ovarian cancer samples was missense mutation. (4) MTHFD2 knockdown inhibited proliferation, migration, invasion, as well as the expression of MOB1A in vitro. CONCLUSION: MTHFD2, as a NAD + -dependent enzyme, accelerated tumor progression by up-regulating MBO1A, suggesting that this protein may be an independent prognostic factor and a potential therapeutic target for future ovarian cancer treatments.

Circular RNA circCCDC85A inhibits breast cancer progression via acting as a miR-550a-5p sponge to enhance MOB1A expression.

BACKGROUND: A growing body of evidence indicates that abnormal expression of circular RNAs (circRNAs) plays a crucial role by acting as molecular sponges of microRNAs (miRNAs) in various diseases, including cancer. In this study, we explored whether circCCDC85A could function as a miR-550a-5p sponge and influence breast cancer progression. METHODS: We detected the expression of circCCDC85A in breast cancer tissues and cells using fluorescence in situ hybridization (FISH) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). CCK-8 and colony formation assay were used to detect the proliferative ability of breast cancer cells. Wound healing assay and transwell migration and invasion assays were used to detect the migrative and invasive abilities of breast cancer cells. We also examined the interactions between circCCDC85A and miR-550a-5p using FISH, RNA-binding protein immunoprecipitation (RIP), and luciferase reporter assay. Moreover, we performed luciferase reporter assay, qRT-PCR, and Western blot to confirm the direct targeting of miR-550a-5p to MOB1A. RESULTS: The expression of circCCDC85A in breast cancer tissues was obviously lower than that in normal breast tissues. Over-expression of circCCDC85A substantially inhibited the proliferative, migrative, and invasive ability of breast cancer cells, while knocking down of circCCDC85A enhanced the aforementioned properties of breast cancer cells. Moreover, enforced expression of circCCDC85A inhibits the oncogenic activity of miR-550a-5p and increases the expression of MOB1A targeted by miR-550a-5p. Further molecular mechanism research showed that circCCDC85A may act as a molecular sponge for miR-550a-5p, thus restoring miR-550a-5p-mediated targeting repression of tumor suppressor MOB1A in breast cancer cells. CONCLUSION: Our findings provide novel evidence that circCCDC85A inhibits the progression of breast cancer by functioning as a molecular sponge of miR-550a-5p to enhance MOB1A expression.

Characterization of a MOB1 Homolog in the Apicomplexan Parasite Toxoplasma gondii.

Monopolar spindle One Binder1 (MOB1) proteins are conserved components of the tumor-suppressing Hippo pathway, regulating cellular processes such as cytokinesis. Apicomplexan parasites present a life cycle that relies on the parasites' ability to differentiate between stages and regulate their proliferation; thus, Hippo signaling pathways could play an important role in the regulation of the apicomplexan life cycle. Here, we report the identification of one MOB1 protein in the apicomplexan Toxoplasma gondii. To characterize the function of MOB1, we generated gain-of-function transgenic lines with a ligand-controlled destabilization domain, and loss-of-function clonal lines obtained through CRISPR/Cas9 technology. Contrary to what has been characterized in other eukaryotes, MOB1 is not essential for cytokinesis in T. gondii. However, this picture is complex since we found MOB1 localized between the newly individualized daughter nuclei at the end of mitosis. Moreover, we detected a significant delay in the replication of overexpressing tachyzoites, contrasting with increased replication rates in knockout tachyzoites. Finally, using the proximity-biotinylation method, BioID, we identified novel members of the MOB1 interactome, a probable consequence of the observed lack of conservation of some key amino acid residues. Altogether, the results point to a complex evolutionary history of MOB1 roles in apicomplexans, sharing properties with other eukaryotes but also with divergent features, possibly associated with their complex life cycle.

TAZ inhibits acinar cell differentiation but promotes immature ductal cell proliferation in adult mouse salivary glands.

There are currently no treatments for salivary gland diseases, making it vital to understand signaling mechanisms operating in acinar and ductal cells so as to develop regenerative therapies. To date, little work has focused on elucidating the signaling cascades controlling the differentiation of these cell types in adult mammals. To analyze the function of the Hippo-TAZ/YAP1 pathway in adult mouse salivary glands, we generated adMOB1DKO mice in which both MOB1A and MOB1B were TAM-inducibly deleted when the animals were adults. Three weeks after TAM treatment, adMOB1DKO mice exhibited smaller submandibular glands (SMGs) than controls with a decreased number of acinar cells and an increased number of immature dysplastic ductal cells. The mutants suffered from reduced saliva production accompanied by mild inflammatory cell infiltration and fibrosis in SMGs, similar to the Sjogren's syndrome. MOB1-deficient acinar cells showed normal proliferation and apoptosis but decreased differentiation, leading to an increase in acinar/ductal bilineage progenitor cells. These changes were TAZ-dependent but YAP1-independent. Biochemically, MOB1-deficient salivary epithelial cells showed activation of the TAZ/YAP1 and ß-catenin in ductal cells, but reduced SOX2 and SOX10 expression in acinar cells. Thus, Hippo-TAZ signaling is critical for proper ductal and acinar cell differentiation and function in adult mice.

Activation of the Legionella pneumophila LegK7 Effector Kinase by the Host MOB1 Protein.

Legionella pneumophila infects alveolar macrophages and can cause life-threatening pneumonia in humans. Upon internalization into the host cell, L. pneumophila injects numerous effector proteins into the host cytoplasm as a part of its pathogenesis. LegK7 is an effector kinase of L. pneumophila that functionally mimics the eukaryotic Mst kinase and phosphorylates the host MOB1 protein to exploit the Hippo pathway. To elucidate the LegK7 activation mechanism, we determined the apo structure of LegK7 in an inactive form and performed a comparative analysis of LegK7 structures. LegK7 is a non-RD kinase that contains an activation segment that is ordered, irrespective of stimulation, through a unique ß-hairpin-containing segment, and it does not require phosphorylation of the activation segment for activation. Instead, bacterial LegK7 becomes an active kinase via its heterologous molecular interaction with the host MOB1 protein. MOB1 binding triggers reorientation of the two lobes of the kinase domain, as well as a structural change in the interlobe hinge region in LegK7, consequently reshaping the LegK7 structure into an ATP binding-compatible closed conformation. Furthermore, we reveal that LegK7 is an atypical kinase that contains an N-terminal capping domain and a hydrophilic interlobe linker motif, which play key roles in the MOB1-induced activation of LegK7.

A Novel Hyperactive Nud1 Mitotic Exit Network Scaffold Causes Spindle Position Checkpoint Bypass in Budding Yeast.

Mitotic exit is a critical cell cycle transition that requires the careful coordination of nuclear positioning and cyclin B destruction in budding yeast for the maintenance of genome integrity. The mitotic exit network (MEN) is a Ras-like signal transduction pathway that promotes this process during anaphase. A crucial step in MEN activation occurs when the Dbf2-Mob1 protein kinase complex associates with the Nud1 scaffold protein at the yeast spindle pole bodies (SPBs; centrosome equivalents) and thereby becomes activated. This requires prior priming phosphorylation of Nud1 by Cdc15 at SPBs. Cdc15 activation, in turn, requires both the Tem1 GTPase and the Polo kinase Cdc5, but how Cdc15 associates with SPBs is not well understood. We have identified a hyperactive allele of NUD1, nud1-A308T, that recruits Cdc15 to SPBs in all stages of the cell cycle in a CDC5-independent manner. This allele leads to early recruitment of Dbf2-Mob1 during metaphase and requires known Cdc15 phospho-sites on Nud1. The presence of nud1-A308T leads to loss of coupling between nuclear position and mitotic exit in cells with mispositioned spindles. Our findings highlight the importance of scaffold regulation in signaling pathways to prevent improper activation.

MOB1A regulates glucose deprivation-induced autophagy via IL6-STAT3 pathway in gallbladder carcinoma.

MOB kinase activator 1A (MOB1A) plays an important role in many diseases and cancers. Here, we observed that MOB1A was substantially overexpressed in gallbladder carcinoma (GBC) tissues compared with nontumor tissues. The high expression of MOB1A was closely associated with poor survival in patients with GBC at advanced TNM stages. Furthermore, our study indicated that MOB1A promoted autophagy by activating the IL6/STAT3 signaling pathway and regulating the chemosensitivity to gemcitabine under glucose deprivation conditions both in vitro and in vivo. In conclusion, these findings suggested that MOB1A is critical for the development of GBC via the MOB1A-IL6/STAT3-autophagy axis.

MOB1 Inhibits Malignant Progression of Colorectal Cancer by Targeting PAK2.

OBJECTIVE: We aimed at studying the mechanism of MOB1 inhibiting the proliferation and metastasis of colorectal cancer (CRC), to provide a new guidance for the early diagnosis and treatment of CRC. METHODS: MOB1 expression level in 68 pairs of CRC tissues and adjacent ones was detected by quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and the associations between the expression level of MOB1 and the clinicopathological indicators as well as the prognosis of CRC patients were analyzed. After constructing CRC cell lines that stably overexpressing or silencing MOB1, the changes of cell proliferation and metastasis ability were examined by Cell Counting Kit (CCK-8) and Transwell assay. In addition, the interaction between MOB1 and PAK2 and how the these two genes affect the biological functions of CRC cell lines were investigated by luciferase assay, qRT-PCR and Western Blot experiments. RESULTS: Our data showed that MOB1 expression level in CRC tissues was remarkably lower than that in adjacent ones. In comparison to patients of the group of high MOB1 expression, these patients of low MOB1 expression group showed higher incidence of distant or lymph node metastasis and lower survival rate. Cell functional experiments revealed that overexpression of MOB1 markedly attenuated the proliferation and migration ability of CRC cell lines compared to the NC group; In contrast, knockdown of MOB1 enhanced the above-mentioned cell abilities compared to anti-NC group. Luciferase assay verified an interaction between MOB1 and PAK2; and Western blot analysis showed a negative correlation between the expression of the MOB1 and PAK2 protein levels in CRC tissues. Subsequently, we demonstrated that MOB1 interacted with PAK2 to regulate its expression and affected the proliferation and migration capacity of CRC cell lines in vitro. CONCLUSION: In summary, the lowly expressed MOB1 in CRC tissues and cell lines may accelerate the proliferation and migration through modulating PAK2 expression.

Association of Mps one binder kinase activator 1 (MOB1) expression with poor disease-free survival in individuals with non-small cell lung cancer.

BACKGROUND: Mps one binder kinase activator 1 (MOB1) is a core component of the Hippo signaling pathway and has been implicated as a tumor suppressor. Here, we evaluated the possible relationship of MOB1 expression in non-small cell lung cancer (NSCLC) to prognosis. METHODS: We retrospectively analyzed 205 lung adenocarcinoma patients treated at Kyushu University Hospital between November 2007 and October 2012. MOB1 expression in tumor cells of surgical specimens was evaluated by immunohistochemistry. Invasive activity of NSCLC cell lines in vitro was measured with a transwell assay. RESULTS: Expression of MOB1 was classified as high in 105 of the 205 (51.2%) tumor specimens, and such high expression was significantly associated with poor disease-free survival (P = 0.0161). Among the various clinicopathologic parameters examined, high MOB1 expression was significantly associated only with intratumoral vascular invasion (P = 0.0005). Multivariate analysis also identified high MOB1 expression as a significant independent risk factor for disease-free survival (P = 0.0319). The invasiveness of H1299 cells in vitro was increased or attenuated by overexpression or knockdown of MOB1, respectively. CONCLUSIONS: Our results suggest that MOB1 might promote early recurrence of NSCLC by increasing vascular invasion by tumor cells. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: We found that high MOB1 expression in surgical specimens of lung adenocarcinoma was associated with poor disease-free survival and with intratumoral vascular invasion. MOB1 expression also promoted the invasiveness of NSCLC cells in vitro. WHAT THIS STUDY ADDS: Our results thus suggest that high MOB1 expression is a risk factor for early postoperative recurrence in lung adenocarcinoma.

RNA-binding protein Musashi2 regulates Hippo signaling via SAV1 and MOB1 in pancreatic cancer.

Musashi 2 (MSI2), a member of the Musashi RNA-binding family, is reported to be an oncoprotein in pancreatic ductal adenocarcinoma (PDAC), but the mechanisms of MSI2 in the development and progression of PDAC have not been fully demonstrated. In this research, we studied the clinical significance, biologic effects and the underlying mechanism of MSI2 in the progression of PDAC. The expression of MSI2, Mps-binding protein 1 (MOB1) and Salvador family WW domain-containing protein 1 (SAV1) in PDAC tissues were analyzed immunohistochemically. The biologic effects of MSI2 regarding PDAC cell proliferation, migration and invasion were studied using gain- and loss-of-function assays. MSI2 regulated Hippo signaling pathway via SAV1 and MOB1 was tested in several PDAC cell lines, and the mechanisms were studied using molecular biologic methods. The expression of MSI2 was significantly increased in PDAC cell lines and tissues, and positively associated with tumor poorer differentiation, lymph nodes metastasis and TNM stages. Overexpression of MSI2 promoted PDAC cells proliferation, migration and invasion. Further studies demonstrated that MSI2 regulated the Hippo signaling pathway via directly binding to the mRNAs of SAV1 and MOB1, and controlled the translation and stability of SAV1 and the translation of MOB1. This study demonstrated that MSI2 regulated the Hippo signaling pathway via suppressing SAV1 and MOB1 at post-transcriptional level and promoted PDAC progression.

O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity.

The Hippo pathway controls organ size and tissue homeostasis by regulating cell proliferation and apoptosis. The LATS-mediated negative feedback loop prevents excessive activation of the effectors YAP/TAZ, maintaining homeostasis of the Hippo pathway. YAP and TAZ are hyperactivated in various cancer cells which lead to tumor growth. Aberrantly increased O-GlcNAcylation has recently emerged as a cause of hyperactivation of YAP in cancer cells. However, the mechanism, which induces hyperactivation of TAZ and blocks LATS-mediated negative feedback, remains to be elucidated in cancer cells. This study found that in breast cancer cells, abnormally increased O-GlcNAcylation hyperactivates YAP/TAZ and inhibits LATS2, a direct negative regulator of YAP/TAZ. LATS2 is one of the newly identified O-GlcNAcylated components in the MST-LATS kinase cascade. Here, we found that O-GlcNAcylation at LATS2 Thr436 interrupted its interaction with the MOB1 adaptor protein, which connects MST to LATS2, leading to activation of YAP/TAZ by suppressing LATS2 kinase activity. LATS2 is a core component in the LATS-mediated negative feedback loop. Thus, this study suggests that LATS2 O-GlcNAcylation is deeply involved in tumor growth by playing a critical role in dysregulation of the Hippo pathway in cancer cells.

PINK1-Dependent Mitophagy Regulates the Migration and Homing of Multiple Myeloma Cells via the MOB1B-Mediated Hippo-YAP/TAZ Pathway.

The roles of mitochondrial dysfunction in carcinogenesis remain largely unknown. The effects of PTEN-induced putative kinase 1 (PINK1)-dependent mitophagy on the pathogenesis of multiple myeloma (MM) are determined. The levels of the PINK1-dependent mitophagy markers PINK1 and parkin RBR E3 ubiquitin protein ligase (PARK2) in CD138+ plasma cells are reduced in patients with MM and correlate with clinical outcomes in myeloma patients. Moreover, the induction of PINK1-dependent mitophagy with carbonylcyanide-m-chlorophenylhydrazone (CCCP) or salinomycin, or overexpression of PINK1 leads to inhibition of transwell migration, suppression of myeloma cell homing to calvarium, and decreased osteolytic bone lesions. Furthermore, genetic deletion of pink1 accelerates myeloma development in a spontaneous X-box binding protein-1 spliced isoform (XBP-1s) transgenic myeloma mouse model and in VK*MYC transplantable myeloma recipient mice. Additionally, treatment with salinomycin shows significant antimyeloma activities in vivo in murine myeloma xenograft models. Finally, the effects of PINK1-dependent mitophagy on myeloma pathogenesis are driven by the activation of the Mps one binder kinase activator (MOB1B)-mediated Hippo pathway and the subsequent downregulation of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) expression. These data provide direct evidence that PINK1-dependent mitophagy plays a critical role in the pathogenesis of MM and is a potential therapeutic target.

Lysine demethylase 2 (KDM2B) regulates hippo pathway via MOB1 to promote pancreatic ductal adenocarcinoma (PDAC) progression.

BACKGROUND: Mps1 binding protein (MOB1) is one of the core components of the mammalian Hippo pathway and plays important roles in cancer development. However, its expression, function and regulation in pancreatic ductal adenocarcinoma (PDAC) have not been revealed yet. METHODS: The expression of MOB1 and lysine demethylase 2B (KDM2B) in PDAC and adjacent normal pancreas tissues were measured. Also, the underlying mechanisms of altered MOB1 expression and its impact on PDAC biology were investigated. RESULTS: We revealed for the first time that MOB1 was decreased expression in PDAC and was a statistically significant independent predictor of poor survival, and restored expression of MOB1 suppressed the proliferation, migration and invasion of PDAC cells. Further studies demonstrated that KDM2B directly bound to the promoter region of MOB1, and suppressed the promoter activity of MOB1 and transcriptionally inhibited the MOB1 expression. Furthermore, KDM2B regulated Hippo pathway and promoted PDAC proliferation, migration and invasion via MOB1. CONCLUSION: This study demonstrated the mechanism and roles of a novel KDM2B/MOB1/Hippo signaling in PDAC progression.

Kindlin-2 Inhibits the Hippo Signaling Pathway by Promoting Degradation of MOB1.

The Hippo signaling pathway plays a key role in development and cancer progression. However, molecules that intrinsically inhibit this pathway are less well known. Here, we report that the focal adhesion molecule Kindlin-2 inhibits Hippo signaling by interacting with and degrading MOB1 and promoting the interaction between MOB1 and the E3 ligase praja2. Kindlin-2 thus inhibits the phosphorylation of LATS1 and YAP and promotes YAP translocation into the nucleus, where it activates downstream Hippo target gene transcription. Kindlin-2 depletion activates Hippo/YAP signaling and alleviates renal fibrosis in Kindlin-2 knockout mice with unilateral ureteral occlusion (UUO). Moreover, Kindlin-2 levels are negatively correlated with MOB1 and phosphorylated (p) YAP in samples from patients with renal fibrosis. Altogether, these results demonstrate that Kindlin-2 inhibits Hippo signaling through degradation of MOB1. A specific long-lasting siRNA against Kindlin-2 effectively alleviated UUO-induced renal fibrosis and could be a potential therapy for renal fibrosis.

MOB1 regulates thymocyte egress and T-cell survival in mice in a YAP1-independent manner.

Mammalian STE20-like protein kinase 1/2 (MST1/2) and nuclear Dbf2-related kinase 1/2 (NDR1/2) are core components of Hippo signaling that are also known to be important regulators of lymphocyte trafficking. However, little is understood about the roles of other Hippo pathway molecules in these cells. Here, we present the first analysis of the function of Mps one binder kinase activator-1 (MOB1) in T lymphocytes in vivo. T-cell-specific double knockout (DKO) of MOB1A/B in mice [tMob1 DKO mice] reduces the number of naïve T cells in both the circulation and secondary lymphoid organs, but leads to an accumulation of CD4+ CD8- and CD4- CD8+ single-positive (SP) cells in the thymus. In vitro, naïve MOB1A/B-deficient T cells show increased apoptosis and display impaired trafficking capacity in response to the chemokine CCL19. These defects are linked to suppression of the activation of MST and NDR kinases, but are independent of the downstream transcriptional co-activator Yes-associated protein 1 (YAP1). Thus, MOB1 proteins play an important role in thymic egress and T-cell survival that is mediated by a pathway other than conventional Hippo-YAP1 signaling.