TRIM22 promotes the proliferation of glioblastoma cells by activating MAPK signaling and accelerating the degradation of Raf-1

Abstract

The tripartite motif (TRIM) 22 and mitogen-activated protein kinase (MAPK) signaling pathways play critical roles in the growth of glioblastoma (GBM). However, the molecular mechanism underlying the relationship between TRIM22 and MAPK signaling remains unclear. Here, we found that TRIM22 binds to exon 2 of the sphingosine kinase 2 (SPHK2) gene. An ERK1/2-driven luciferase reporter construct identified TRIM22 as a potential activator of MAPK signaling. Knockout and overexpression of TRIM22 regulate the inhibition and activation of MAPK signaling through the RING-finger domain. TRIM22 binds to Raf-1, a negative regulator of MAPK signaling, and accelerates its degradation by inducing K48-linked ubiquitination, which is related to the CC and SPRY domains of TRIM22 and the C1D domain of Raf-1. In vitro and in vivo, an SPHK2 inhibitor (K145), an ERK1/2 inhibitor (selumetinib), and the nonphosphorylated mutant Raf-1^S338A inhibited GBM growth. In addition, deletion of the RING domain and the nuclear localization sequence of TRIM22 significantly inhibited TRIM22-induced proliferation of GBM cells in vivo and in vitro. In conclusion, our study showed that TRIM22 regulates SPHK2 transcription and activates MAPK signaling through posttranslational modification of two critical regulators of MAPK signaling in GBM cells.

Brain cancer: A protein and pathway to target glioblastoma

Key aspects of the role of the multi-functional protein TRIM22 in promoting the proliferation of glioblastoma, the most common malignant brain tumor in adults, have been identified in human glioblastoma cells and laboratory mice. Xiaofan Jiang, Zhou Fei and colleagues at the Air Force Medical University in Xi’an, China, revealed how TRIM22 activates MAPK signaling, a pathway of interacting proteins that controls cell growth and development. TRIM22 was also found to accelerate the degradation of a cell-regulating protein called Raf-1. This occurs when TRIM22 binds to and controls the expression of a gene involved in MAPK signaling, and also when it directly interacts with Raf-1 and another key protein. Inhibiting TRIM22 with a candidate drug suggested that targeting it or the processes it affects could yield new treatments for glioblastoma.