SPRED2 (Sprouty Related EVH1 Domain Containing 2)

The current study revealed a novel SPRED2/p53/miR-506-3p/KLF4 axis through which SPRED2 contributes to the suppression of HCC cell stemness and provides a potential new target to prevent HCC progression.

Bone marrow-derived macrophages from Spred2-/- mice produced higher levels of TNFα in response to cisplatin compared with control cells, and this increase was markedly suppressed by U0126. These findings indicate that endogenous SPRED2 protects kidneys from cisplatin-induced AKI by limiting ERK activation, tubular apoptosis, and TNFα-mediated inflammation.

By database analyses, both NF1 and SPRED2 mRNA levels were reduced in BC tissues, and luminal A BC patients with high expression of both NF1 and SPRED2 mRNA exhibited improved relapse-free survival. These results suggest a critical role for the NF-SPRED2 axis in BC progression and highlight it as a potential therapeutic target.

These findings provide a foundation for future clinical studies and targeted interventions to enhance recovery from PFP. Future research should focus on human sample validation to enhance clinical translation.

On the other hand, MD simulations also identified long-range structural rearrangements of the SPRED2 EVH-1 domain, which might be relevant for an aberrant folding of the mutant driving the previously documented accelerated degradation. Overall, the performed MD simulations suggest the occurrence of multiple intramolecular and intermolecular structural perturbations driven by the Leu100Pro change that likely contribute to its LoF behavior.

Moreover, after TMEV infection, ERK phosphorylation was altered by the L protein in a DDVF-dependent manner. Taken together, our data suggest that, in addition to retargeting RSKs toward unconventional substrates, pathogen proteins carrying a DDVF-like motif can compete with endogenous DDVF-containing proteins for RSK binding, thereby altering the regulation of the RAS-ERK MAP kinase pathway.

In vitro, SPRED2 deletion increased cell proliferation, migration and invasion of three LUAD cell lines (A549:KRAS mutation, H1993:METamplification, and HCC4006:EGFR mutation), whereas SPRED2 overexpression decreased these responses. Thus, SPRED2 appears to be a regulator of LUAD progression and a potential target for the treatment of LUAD.

Finally, hepatic autophagy was impaired in the liver of SPRED2-deficient mice with hepatic lipid droplet accumulation in response to starvation. These results indicate that SPRED2 is a critical regulator of autophagy not only in HCC cells, but also in hepatocytes, and thus the manipulation of this process may provide new insights into liver pathology.

Clones with mutations in these genes grow in frequency and size with age, comparable to classical CH drivers. They correlate with heightened risk of infection, death and hematological malignancy, highlighting the significance of these additional genes in the aging process.

Our study may shed new light on the pathogenesis of NF1-associated neurofibromas and will hopefully contribute to the development of personalized care for this deleterious and life-threatening condition.

SPRED2-KO cells demonstrated a higher ability to form spheres and colonies, expressed higher levels of stemness markers and were more resistant to cisplatin...Finally, the levels of SPRED2 in clinical HCC tissues were significantly lower than those in adjacent non-HCC tissues and were negatively associated with progression-free survival. Thus, the downregulation of SPRED2 in HCC promotes EMT and stemness through the activation of the ERK1/2 pathway, and leads to more malignant phenotypes.