Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Schwannoma tumors, which occur sporadically and in patients with neurofibromatosis, account for 8% of intracranial tumors and can only be treated by surgical removal. Most schwannomas have biallelic mutations in the NF2 tumor suppressor gene. We previously showed that schwannoma-derived Schwann cells exhibit membrane ruffling and aberrant cell spreading when plated onto laminin, indicative of fundamental F-actin cytoskeletal defects. Here we expand these observations to a large group of sporadic and NF2-related tumors and extend them to schwannomatosis-derived tumors. Mutation at NF2 correlated with F-actin abnormalities, but the extent of morphological change did not correlate with the type of NF2 mutation. We used a recently described molecular strategy, TAT-mediated protein transfer, to acutely introduce the NF2 protein, merlin, into primary human schwannoma cells in an attempt to reverse the cytoskeletal phenotype. Abnormal ruffling and cell spreading by cells with identified NF2 mutations were rapidly reversed by introduction of TAT-merlin. The effect is specific to TAT-merlin isoform 1, the growth-suppressive isoform of merlin. TAT-merlin isoform 2, a TAT-merlin mutant (L64P), and merlin lacking TAT were ineffective in reversing the cytoskeletal phenotype. Results show that merlin isoform 1 is sufficient to restore normal actin organization in NF2-deficient human tumor cells, demonstrating a key role for merlin in the NF2 phenotype. These results lay the foundation for epigenetic complementation studies in NF2 mouse models and possibly for experiments to evaluate the utility of merlin transduction into patients as protein therapy.
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PMID:The neurofibromatosis type 2 gene product, merlin, reverses the F-actin cytoskeletal defects in primary human Schwannoma cells. 1180 6

Although multiple determinants for establishing polarity in membranes of epithelial cells have been identified, the mechanism for maintaining apicobasal polarity is not fully understood. Here, we show that the conserved Hippo kinase pathway plays a role in the maintenance of apicobasal polarity in the developing intestine of Caenorhabditis elegans We screened suppressors of the mutation in wts-1-the gene that encodes the LATS kinase homolog, deficiency of which leads to disturbance of the apicobasal polarity of the intestinal cells and to eventual death of the organism. We identified several alleles of yap-1 and egl-44 that suppress the effects of this mutation. yap-1 encodes a homolog of YAP/Yki, and egl-44 encodes a homolog of TEAD/Sd. WTS-1 bound directly to YAP-1 and inhibited its nuclear accumulation in intestinal cells. We also found that NFM-1, which is a homolog of NF2/Merlin, functioned in the same genetic pathway as WTS-1 to regulate YAP-1 to maintain cellular polarity. Transcriptome analysis identified several target candidates of the YAP-1-EGL-44 complex including TAT-2, which encodes a putative P-type ATPase. In summary, we have delineated the conserved Hippo pathway in C. elegans consisting of NFM-1-WTS-1-YAP-1-EGL-44 and proved that the proper regulation of YAP-1 by upstream NFM-1 and WTS-1 is essential for maintenance of apicobasal membrane identities of the growing intestine.
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PMID:The Hippo Pathway Is Essential for Maintenance of Apicobasal Polarity in the Growing Intestine of Caenorhabditis elegans. 3135 32