3,891 research outputs found
Fibroblasts in head neck squamous cell carcinoma associated with perineural invasion have high level nuclear Yes-Associated Protein (YAP) expression
No full textPaul A. Reynolds, PhD, is supported by the Melville Trust for the Care and cure of Cancer.We retrospectively studied the expression of Yes-associated protein (YAP) using immunohistochemical staining in 10 cases of head and neck squamous cell carcinoma with associated perineural invasion. We find that fibroblasts in areas associated with perineural invasion show higher levels of nuclear YAP compared to fibroblasts in the stroma of normal mucosa, with a median cell count of 35.4 per high-power field in the former and 3.9 in the latter. No differences were observed between the expression of YAP phosphorylated at Ser127 in the tumoral stroma compared to that in the normal mucosa, with a median cell count expression of 4.9 in the former versus 5.0 in the latter. Therefore, a strong and increased nuclear YAP expression in fibroblasts associated with perineural invasion in head and neck squamous cell carcinoma suggests that YAP-mediated transcription programs in these fibroblasts may contribute to perineural invasion.Peer reviewe
Willin, an upstream component of the Hippo signaling pathway, orchestrates mammalian peripheral nerve fibroblasts
No full textWillin/FRMD6 was first identified in the rat sciatic nerve, which is composed of neurons, Schwann cells, and fibroblasts. Willin is an upstream component of the Hippo signaling pathway, which results in the inactivation of the transcriptional coactivator YAP through Ser127 phosphorylation. This in turn suppresses the expression of genes involved in cell growth, proliferation and cancer development ensuring the control of organ size, cell contact inhibition and apoptosis. Here we show that in the mammalian sciatic nerve, Willin is predominantly expressed in fibroblasts and that Willin expression activates the Hippo signaling cascade and induces YAP translocation from the nucleus to the cytoplasm. In addition within these cells, although it inhibits cellular proliferation, Willin expression induces a quicker directional migration towards scratch closure and an increased expression of factors linked to nerve regeneration. These results show that Willin modulates sciatic nerve fibroblast activity indicating that Willin may have a potential role in the regeneration of the peripheral nervous system.Peer reviewe
African and Levantine Origins of Pakistani YAP+ Y Chromosomes
No full textWe surveyed 9 Pakistani subpopulations for variation on the nonrecombining portion of the Y chromosome. The polymorphic systems examined were the Y-chromosome Alu insertion polymorphism (YAP) at DYS287, 5 single nucleotide polymorphisms, and the tetranucleotide microsatellite DYS19. Y chromosomes carrying the YAP element (YAP+) were found in populations from southwestern Pakistan at frequencies ranging from 2% to 8%, whereas northeastern populations appeared to lack YAP+ chromosomes. In contrast to other South Asian populations, several Pakistani subpopulations had a high frequency of the DYS19*B allele, the most frequent allele in West Asian, North African, and European populations. The combination of alleles at all polymorphic sites gave rise to 9 YAP-DYS19 combination haplotypes in Pakistani populations, including YAP+ haplotypes 4-A, 4-B, 5-C, and 5-E. We hypothesize that the geographic distributions of YAP+ haplotypes 4 and 5 trace separate migratory routes to Pakistan: YAP+ haplotype 5 may have entered Pakistan from the Arabian Peninsula by means of migrations across the Gulf of Oman, whereas males possessing YAP+ haplotype 4 may have traveled over land from the Middle East. These inferences are consistent with ethnohistorical data suggesting that Pakistan’s ethnic groups have been influenced by migrations from both African and Levantine source populations
Expanding the Hippo pathway : hMOB3 modulates apoptotic MST1 signaling and supports tumor growth in glioblastoma
No full textProtein kinases are critical players of signal transduction pathways involved in development, physiological and pathological processes. Deregulation of protein kinase signaling is found to be causal or related to varieties of human diseases, such as cancer, cardiovascular disease and diabetes. The human genome encodes 518 protein kinases. Approximately 60 out of them belong to the AGC group of Serine/Threonine protein kinases, including the ste20 like MST kinase family and NDR kinase family. Members of these families are highly conserved from yeast to men and regulate essential processes such as growth, proliferation and apoptosis. The Hippo pathway is a recently identified tumor suppressive network, where the MST-NDR family kinases form a kinase cascade regulating the downstream signaling through the effector YAP/TAZ.
In addition to signaling through the NDR family kinases, the Hippo/MST kinases also control cell apoptosis bypass these classical effectors YAP/TAZ. Despite the fact that JNK, FOXO3, H2B are well characterized downstream targets of apoptotic MST kinases, the regulatory mechanisms of apoptotic MST signaling are still largely unknown.
The human MOB family consists of six members encoded by six different genes (hMOB1A, -1B, -2, -3A, -3B and -3C). While as an activator for hMOB1A/B in MST-LATS/NDR kinase cascade, hMOB2 is a specific negative regulator of NDR kinase by competing the binding of hMOB1 to NDR kinase. Although hMOB3 family members share higher amino acid identity with hMOB1 than hMOB2, hMOB3 proteins do not interact or (de)activate NDR family kinases. Hence, the functions of hMOB3A/B/C are completely undefined.
A previous microarray study performed in the lab indicated that hMOB3 family members were deregulated in glioblastoma. In the present study, we first investigated the pathological roles of human MOB3 proteins and found that hMOB3 is highly upregulated in glioblastoma. Moreover, mRNA expression levels of hMOB3 members correlate with survival, suggesting hMOB3 members as potential prognostic markers. We extended the biochemical analysis by looking for the interaction partners of hMOB3 and demonstrated that hMOB3 binds to MST1 and inhibits the apoptotic cleavage of MST1 kinase. We further verified that hMOB3 promotes tumorigenesis of gliobalstoma cells in vivo by a U87MG derived flank model. Taken together, our results suggest that manipulate hMOB3 might represent a therapeutic strategy in malignant gliomas
Metal content and biochemical analyses of a recombinant collagenase PrtV from Vibrio parahaemolyticus
No full textYAP promotes myogenic differentiation via the MEK5-ERK5 pathway
No full text[[abstract]]Yes-associated protein (YAP) is a transcriptional coactivator in the Hippo pathway that regulates cell proliferation, differentiation, and apoptosis. The MEK5/ERK5 MAPK cascade is essential for the early step of myogenesis. In this study, we generated C2C12 stable cell lines that expressed YAP (C2C12-YAP cells) and found that ERK5 and MEK5 were activated in C2C12-YAP cells compared with control C2C12 (C2C12-vector) cells. C2C12-YAP stable cells also differentiated into myotubes better than C2C12-vector cells, and expressed elevated levels of myogenin, a transcription factor that regulates myogenesis, as well as elevated levels of myosin heavy chain, a skeletal muscle marker. Western blot analysis revealed that Src and c-Abl (Abelson murine leukemia viral oncogene homolog 1) activation were enhanced in C2C12-YAP cells. Conversely, treatment of inhibitors of c-Abl, Src, or MEK5 inhibited activation of MEK5 and ERK5 and myogenesis of C2C12 myoblasts. Specific interactions between YAP and proteins in the ERK5 pathway, such as MEK kinase 3 (MEKK3) and ERK5, were illustrated by coimmunoprecipitation experiments. MEKK3 contains the PPGY motif (aa 178-181), which may interact with YAP. Site-directed mutagenesis experiments revealed that expression of MEKK3 Y181F mutant inhibited MEK5/ERK5 activation and myogenic differentiation. These results suggest that YAP promotes muscle differentiation by activating the Abl/Src/MEKK3/MEK5/ERK5 kinase cascade.-Chen, T.-H., Chen, C.-Y., Wen, H.-C., Chang, C.-C., Wang, H.-D., Chuu, C.-P., Chang, C.-H. YAP promotes myogenic differentiation via the MEK5-ERK5 pathway
Enigma proteins regulate YAP mechanotransduction
No full textHuman cells can sense mechanical stress acting upon integrin adhesions and respond by sending the YAP (also known as YAP1) and TAZ (also known as WWTR1) transcriptional co-activators to the nucleus to drive TEAD-dependent transcription of target genes. How integrin signaling activates YAP remains unclear. Here, we show that integrin-mediated mechanotransduction requires the Enigma and Enigma-like proteins (PDLIM7 and PDLIM5, respectively; denoted for the family of PDZ and LIM domain-containing proteins). YAP binds to PDLIM5 and PDLIM7 (hereafter PDLIM5/7) via its C-terminal PDZ-binding motif (PBM), which is essential for full nuclear localization and activity of YAP. Accordingly, silencing of PDLIM5/7 expression reduces YAP nuclear localization, tyrosine phosphorylation and transcriptional activity. The PDLIM5/7 proteins are recruited from the cytoplasm to integrin adhesions and F-actin stress fibers in response to force by binding directly to the key stress fiber component α-actinin. Thus, forces acting on integrins recruit Enigma family proteins to trigger YAP activation during mechanotransduction.This article has an associated First Person interview with the first author of the paper
Distinct fibroblast subsets regulate lacteal integrity through YAP/TAZ-induced VEGF-C in intestinal villi
No full textEmerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. However, the extent of heterogeneity within the villi stromal compartment and how IntSCs regulate the structure and function of specialized intestinal lymphatic capillary called lacteal remain elusive. Here we show that selective hyperactivation or depletion of YAP/TAZ in PDGFR beta(+) IntSCs leads to lacteal sprouting or regression with junctional disintegration and impaired dietary fat uptake. Indeed, mechanical or osmotic stress regulates IntSC secretion of VEGF-C mediated by YAP/TAZ. Single-cell RNA sequencing delineated novel subtypes of villi fibroblasts that upregulate Vegfc upon YAP/TAZ activation. These populations of fibroblasts were distributed in proximity to lacteal, suggesting that they constitute a peri-lacteal microenvironment. Our findings demonstrate the heterogeneity of IntSCs and reveal that distinct subsets of villi fibroblasts regulate lacteal integrity through YAP/TAZ-induced VEGF-C secretion, providing new insights into the dynamic regulatory mechanisms behind lymphangiogenesis and lymphatic remodeling.Peer reviewe
Enigma proteins regulate YAP mechanotransduction
No full textHuman cells can sense mechanical stress acting upon integrin adhesions and respond by sending the YAP (also known as YAP1) and TAZ (also known as WWTR1) transcriptional co-activators to the nucleus to drive TEAD-dependent transcription of target genes. How integrin signaling activates YAP remains unclear. Here, we show that integrin-mediated mechanotransduction requires the Enigma and Enigma-like proteins (PDLIM7 and PDLIM5, respectively; denoted for the family of PDZ and LIM domain-containing proteins). YAP binds to PDLIM5 and PDLIM7 (hereafter PDLIM5/7) via its C-terminal PDZ-binding motif (PBM), which is essential for full nuclear localization and activity of YAP. Accordingly, silencing of PDLIM5/7 expression reduces YAP nuclear localization, tyrosine phosphorylation and transcriptional activity. The PDLIM5/7 proteins are recruited from the cytoplasm to integrin adhesions and F-actin stress fibers in response to force by binding directly to the key stress fiber component α-actinin. Thus, forces acting on integrins recruit Enigma family proteins to trigger YAP activation during mechanotransduction.This article has an associated First Person interview with the first author of the paper
Aberrant transcriptional and post-transcriptional regulation of SPAG5, a YAP-TAZ-TEAD downstream effector, fuels breast cancer cell proliferation
No full textSperm-associated antigen 5 (SPAG5) is an important driver of the cell mitotic spindle required for chromosome segregation and progression into anaphase. SPAG5 has been identified as an important proliferation marker and chemotherapy-sensitivity predictor, especially in estrogen receptor-negative breast cancer subtypes. Here, we report that SPAG5 is a direct target of miR-10b-3p, and its aberrantly high expression associates with poor disease-free survival in two large cohorts of breast cancer patients. SPAG5 depletion strongly impaired cancer cell cycle progression, proliferation, and migration. Interestingly, high expression of SPAG5 pairs with a YAP/TAZ-activated signature in breast cancer patients. Reassuringly, the depletion of YAP, TAZ, and TEAD strongly reduced SPAG5 expression and diminished its oncogenic effects. YAP, TAZ coactivators, and TEAD transcription factors are key components of the Hippo signaling pathway involved in tumor initiation, progression, and metastasis. Furthermore, we report that SPAG5 is a direct transcriptional target of TEAD/YAP/TAZ, and pharmacological targeting of YAP and TAZ severely reduces SPAG5 expression. Collectively, our data uncover an oncogenic feedback loop, comprising miR-10b-3p, SPAG5, and YAP/TAZ/TEAD, which fuels the aberrant proliferation of breast cancer
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