TLN2 functions as a tumor suppressor in clear cell renal cell carcinoma via inactivation of the Wnt/ß-catenin signaling pathway.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent malignancies worldwide, but there is lack of reliable clinical diagnostic biomarkers. We explored the clinical value and functions of Talin 2 (TLN2) in the progression of ccRCC. METHODS: A bioinformatic analysis was performed to determine the clinical value of TLN2 in ccRCC. TLN2 expression was evaluated by immunohistochemistry (IHC), real-time quantitative polymerase chain reaction (RT-qPCR) and western blot in ccRCC tissues and cells. The functions of TLN2 in ccRCC were investigated by both in vivo and in vitro studies. The functions of TLN2 in ccRCC cell proliferation was determined by CCK-8 assays and colony formation assays. Transwell assays and wound healing assays were performed to detect the effects of TLN2 on ccRCC cell invasion and migration abilities. Apoptosis assay and cell cycle analysis were used to determine the influence of TLN2 on ccRCC cell apoptosis and cell cycle. RESULTS: TLN2 was downregulated in ccRCC tissues and cells. Clinically, TLN2 was confirmed to be an independent factor for ccRCC patient prognosis. Results of colony formation and CCK-8 assays showed that TLN2 overexpression inhibited ccRCC cell growth. Moreover, wound healing assays and transwell assays indicated that TLN2 overexpression inhibited ccRCC cell invasion and migration. In vivo assays also indicated that TLN2 played an important role in ccRCC cell growth and metastasis. TLN2 also inhibited cell cycle progression and promoted apoptosis of ccRCC cells. Mechanistically, TLN2 was confirmed to exert anti-ccRCC functions through Wnt/ß-catenin signaling. CONCLUSIONS: TLN2 served as a tumor regulator of ccRCC via Wnt/ß catenin signaling, suggesting that it could be a promising therapeutic and prognostic biomarker for ccRCC.

Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability.

Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1 mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2 and TPM1 variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1 in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2 variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.

Talin in mechanotransduction and mechanomemory at a glance.

Talins are cytoskeletal linker proteins that consist of an N-terminal head domain, a flexible neck region and a C-terminal rod domain made of 13 helical bundles. The head domain binds integrin ß-subunit cytoplasmic tails, which triggers integrin conformational activation to increase affinity for extracellular matrix proteins. The rod domain links to actin filaments inside the cell to transmit mechanical loads and serves as a mechanosensitive signalling hub for the recruitment of many other proteins. The α-helical bundles function as force-dependent switches - proteins that interact with folded bundles are displaced when force induces unfolding, exposing previously cryptic binding sites for other ligands. This leads to the notion of a talin code. In this Cell Science at a Glance article and the accompanying poster, we propose that the multiple switches within the talin rod function to process and store time- and force-dependent mechanical and chemical information.

Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease.

Systematic epistasis analyses in multifactorial disorders are an important step to better characterize complex genetic risk structures. We conducted a hypothesis-free sex-stratified genome-wide screening for epistasis contributing to Alzheimer's disease (AD) susceptibility. We identified a statistical epistasis signal between the single nucleotide polymorphisms rs3733980 and rs7175766 that was associated with AD in males (genome-wide significant pBonferroni-corrected=0.0165). This signal pointed toward the genes WW and C2 domain containing 1, aka KIBRA; 5q34 and TLN2 (talin 2; 15q22.2). Gene-based meta-analysis in 3 independent consortium data sets confirmed the identified interaction: the most significant (pmeta-Bonferroni-corrected=9.02*10-3) was for the single nucleotide polymorphism pair rs1477307 and rs4077746. In functional studies, WW and C2 domain containing 1, aka KIBRA and TLN2 coexpressed in the temporal cortex brain tissue of AD subjects (ß=0.17, 95% CI 0.04 to 0.30, p=0.01); modulated Tau toxicity in Drosophila eye experiments; colocalized in brain tissue cells, N2a neuroblastoma, and HeLa cell lines; and coimmunoprecipitated both in brain tissue and HEK293 cells. Our finding points toward new AD-related pathways and provides clues toward novel medical targets for the cure of AD.