Spred2, or Sprouty-related enabled/vasodilator-stimulated phosphoprotein homology 1 domain containing 2, is an inhibitor of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway [2]. It plays a crucial role in regulating various biological processes, including autophagy, cell proliferation, and differentiation, and is associated with multiple diseases [2,3]. Genetic models, such as knockout mouse models, have been valuable in studying its functions.

In Spred2 -/- mice, cardiac arrhythmias, premature death, and impaired autophagy were observed due to ERK hyperactivation [3]. Spred2 -deficient mice also showed more severe Concanavalin A-induced liver damage with increased interferon-γ production from CD4+ and CD8+ T cells [4]. Moreover, Spred2 -/- mice developed milder pulmonary fibrosis with increased proliferation of bronchial epithelial cells [5]. In contrast, overexpression of wild-type SPRED2 in zebrafish rescued the defects in cell movements induced by spred2a and spred2b knockdown, indicating upregulated RAS-MAPK signaling [1].

In conclusion, Spred2 is a critical regulator of autophagy, T-cell-mediated immune response, and tissue repair. Its deficiency in KO mouse models has been linked to phenotypes related to Noonan syndrome-like features, cardiac arrhythmias, liver damage, and pulmonary fibrosis, highlighting its importance in understanding these disease mechanisms [1,3,4,5].

References:

1. Motta, Marialetizia, Fasano, Giulia, Gredy, Sina, Zenker, Martin, Tartaglia, Marco. 2021. SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype. In American journal of human genetics, 108, 2112-2129. doi:10.1016/j.ajhg.2021.09.007. https://pubmed.ncbi.nlm.nih.gov/34626534/

2. Wang, Tianyi, Gao, Tong, Fujisawa, Masayoshi, Yoshimura, Teizo, Matsukawa, Akihiro. 2024. SPRED2 Is a Novel Regulator of Autophagy in Hepatocellular Carcinoma Cells and Normal Hepatocytes. In International journal of molecular sciences, 25, . doi:10.3390/ijms25116269. https://pubmed.ncbi.nlm.nih.gov/38892460/

3. Ullrich, Melanie, Aßmus, Benjamin, Augustin, Anne Marie, Kuhn, Michaela, Schuh, Kai. 2019. SPRED2 deficiency elicits cardiac arrhythmias and premature death via impaired autophagy. In Journal of molecular and cellular cardiology, 129, 13-26. doi:10.1016/j.yjmcc.2019.01.023. https://pubmed.ncbi.nlm.nih.gov/30771306/

4. Sun, Cuiming, Fujisawa, Masayoshi, Ohara, Toshiaki, Kunkel, Steven L, Matsukawa, Akihiro. 2021. Spred2 controls the severity of Concanavalin A-induced liver damage by limiting interferon-gamma production by CD4+ and CD8+ T cells. In Journal of advanced research, 35, 71-86. doi:10.1016/j.jare.2021.03.014. https://pubmed.ncbi.nlm.nih.gov/35003795/

5. Kawara, Akina, Mizuta, Ryo, Fujisawa, Masayoshi, Yoshimura, Teizo, Matsukawa, Akihiro. 2020. Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin. In Scientific reports, 10, 16490. doi:10.1038/s41598-020-73752-3. https://pubmed.ncbi.nlm.nih.gov/33020583/