| F-box only protein 22(FBXO22)is a member of the F-box protein family that is responsible for recruitment and binding of substrates in the SCF ubiquitin-E3 ligase complex,its biological functions remain largely unknown.Recently,we are devoted to identify new substrates and discover new functions of FBXO22.Interestingly,FBXO22 was found to interact with Serine/threonine kinase STK11(also named as LKB1)by immunoprecipitation and immunofluorescence technology,and the 89-243 aa protein kinase domain of LKB1 is required for its interaction with FBXO22 protein.Based on these findings,we revealed that FBXO22 could regulate Lys-63-linked LKB1 polyubiquitination and inhibit kinase activity of LKB1.It was reported that LKB1 could regulate the mTOR signaling pathway and inhibit cell growth by activating downstream substrate-AMPK.Furthermore,cell proliferation assay,clonal formation assay and the tumor xenograft experiment showed that FBXO22 inhibited the kinase activity of LKB1 and subsequently affected the AMPK-mTOR signaling pathway to rescue the growth inhibition effect caused by LKB1.In addition,we found FBXO22 was highly expressed in lung cancer tumor tissues through TCGA database analysis,immunohistochemical staining amd western blot of a cohort of clinical samples.There are about 15-35% of lung cancer cases with different degrees of LKB1 mutations or deletions.Among the lung adenocarcinoma patients with wild type LKB1,AKaplan-Meier analysis revealed that the patients with FBXO22-high tumors showed significantly poorer overall survival than those with FBXO22-low tumors.Meanwhile,there is no apparent correlation between FBXO22 expression and prognosis among the lung adenocarcinoma patients with LKB1 mutations or deletions.In conclusion,FBXO22 might affect the development and progression of tumors by inhibiting the kinase activity of LKB1.These original data will not only uncover new biological functions of FBXO22,but also provide new molecular basis of precise cancer therapy. |
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