Tumor cells often overexpress immune checkpoint proteins, including CD47, for immune evasion. However, whether or how oncogenic activation of receptor tyrosine kinases, which are crucial drivers in tumor development, regulates CD47 expression is unknown. Here, it is demonstrated that epidermal growth factor receptor (EGFR) activation induces CD47 expression by increasing the binding of c-Src to CD47, leading to c-Src-mediated CD47 Y288 phosphorylation. This phosphorylation inhibits the interaction between the ubiquitin E3 ligase TRIM21 and CD47, thereby abrogating TRIM21-mediated CD47 K99/102 polyubiquitylation and CD47 degradation. Knock-in expression of CD47 Y288F reduces CD47 expression, increases macrophage phagocytosis of tumor cells, and inhibits brain tumor growth in mice. In contrast, knock-in expression of CD47 K99/102R elicits the opposite effects compared to CD47 Y288F expression. Importantly, CD47-SIRPα blockade with an anti-CD47 antibody treatment significantly enhances EGFR-targeted cancer therapy. In addition, CD47 expression levels in human glioblastoma (GBM) specimens correlate with EGFR and c-Src activation and aggravation of human GBM. These findings elucidate a novel mechanism underlying CD47 upregulation in EGFR-activated tumor cells and underscore the role of the EGFR-c-Src-TRIM21-CD47 signaling axis in tumor evasion and the potential to improve the current cancer therapy with a combination of CD47 blockade with EGFR-targeted remedy.

The cerebellum is involved in encoding balance, posture, speed, and gravity during locomotion. However, most studies are carried out on flat surfaces, and little is known about cerebellar activity during free ambulation on slopes. Here, it has been imaged the neuronal activity of cerebellar molecular interneurons (MLIs) and Purkinje cells (PCs) using a miniaturized microscope while a mouse is walking on a slope. It has been found that the neuronal activity of vermal MLIs specifically enhanced during uphill and downhill locomotion. In addition, a subset of MLIs is activated during entire uphill or downhill positions on the slope and is modulated by the slope inclines. In contrast, PCs showed counter-balanced neuronal activity to MLIs, which reduced activity at the ramp peak. So, PCs may represent the ramp environment at the population level. In addition, chemogenetic inactivation of lobule V of the vermis impaired uphill locomotion. These results revealed a novel micro-circuit in the vermal cerebellum that regulates ambulatory behavior in 3D terrains.