CNKSR1, also known as connector enhancer of kinase suppressor of Ras 1, acts as a scaffold component for receptor tyrosine kinase in mitogen-activated protein kinase (MAPK) cascades [2]. It plays a significant role in multiple biological processes and is involved in various signaling pathways, which are crucial for normal cellular functions. Genetic models, such as knockout (KO) or conditional knockout (CKO) mouse models, could potentially provide further insights into its functions.

In HER2-positive breast cancer cells, degradation of RhoB by the CUL3/KCTD10 ubiquitin ligase complex is essential for EGFR and HER2 phosphorylation. CNKSR1 can interact with RhoB-GTP and protein tyrosine phosphatase receptor type H (PTPRH), and the constitutive degradation of RhoB enables CNKSR1 to inactivate EGFR phosphatase activity. Depletion of CUL3 or KCTD10 activates PTPRH through RhoB-GTP binding to CNKSR1 [1]. In pancreatic ductal adenocarcinoma, CNKSR1 acts as a mediator of resistance to MAPK (MEK) inhibition. MEK inhibition in CNKSR1high cancer cells leads to CNKSR1 translocation to the plasma membrane, where it stabilizes phosphorylated AKT, promoting crosstalk between MAPK and AKT signaling [3]. In lung adenocarcinoma, CNKSR1 was identified as a biomarker for "cold" tumor microenvironment, with its mRNA expression negatively correlated with PD-L1 expression and immune cell infiltration [4]. In pancreatic cancer, CNKSR1 expression is increased in tumors compared to normal specimens, and high CNKSR1 expression is associated with better overall survival in patients undergoing resection. The cellular distribution of CNKSR1 is also correlated with nuclear pERK expression [5]. In non-functioning pituitary adenomas, CNKSR1 is downregulated in invasive tumors [6]. In bladder cancer, CNKSR1 was identified as a hub gene associated with the progression and prognosis of MIBC patients, and immunohistochemistry experiments confirmed its role in the tumorigenesis of MIBC [7].

In conclusion, CNKSR1 is a key scaffold protein involved in multiple signaling pathways. Its functions in diseases such as breast cancer, pancreatic cancer, lung adenocarcinoma, non-functioning pituitary adenomas, and bladder cancer have been revealed through various studies. These findings from in vivo-like model-based research provide important insights into the role of CNKSR1 in disease development, potentially guiding the development of new diagnostic and therapeutic strategies for these diseases.