Overexpression of the serine/threonine kinase GLK/ MAP4K3 in human lung cancer is associated with poor prognosis and recurrence, however, the role of GLK in cancer recurrence remains unclear. Here, we report that transgenic GLK promotes tumor metastasis and cell migration through the scaffold protein IQ motif-containing GTPase-activating protein 1(IQGAP1). GLK transgenic mice displayed enhanced distant metastasis. IQGAP1 was identified as a GLK-interacting protein; two proline-rich regions of GLK and the WW domain of IQGAP1 mediated this interaction. GLK and IQGAP1 colocalized at the leading edge including filopodia and lamellipodia of migrating cells. GLK directly phosphorylated IQGAP1 at Ser-480 enhancing Cdc42 activation and subsequent cell migration. GLK-induced cell migration and lung cancer metastasis were abolished by IQGAP1 depletion. Consistently, human NSCLC patient tissues displayed increased phospho-IQGAP1, which correlated with poor survival. Collectively, GLK promotes lung cancer metastasis by binding to, phosphorylating, and activating IQGAP1. Significance: These findings show the critical role of the GLK-IQGAP cascade in cell migration and tumor metastasis, suggesting it as a potential biomarker and therapeutic target for lung cancer recurrence.

Dual-specificity phosphatase (DUSP)14 (also known as MAP-kinase phosphatase 6) inhibits T-cell receptor (TCR) signaling and T-cell–mediated immune responses by inactivation of the TGF-β activated kinase 1 binding protein (TAB1)–TGF-β activated kinase 1 (TAK1) complex and ERK. DUSP14 phosphatase activity is induced by the E3 ligase TNF receptor associated factor (TRAF)2-mediated Lys63-linked ubiquitination. Here we report an interaction between DUSP14 and protein arginine methyltransferase (PRMT)5 by proximity ligation assay; similarly, DUSP14 directly interacted with TAB1 but not TAK1. DUSP14 is methylated by PRMT5 at arginine 17, 38, and 45 residues. The DUSP14 triple-methylation mutant was impaired in PRMT5-mediated arginine methylation, TRAF2-mediated lysine ubiquitination, and DUSP14 phosphatase activity. Consistently, DUSP14 methylation, TRAF2 binding, and DUSP14 ubiquitination were attenuated by PRMT5 short hairpin RNA knockdown. Furthermore, DUSP14 was inducibly interacted with PRMT5 and was methylated during TCR signaling in T cells. Together, these findings reveal a novel regulatory mechanism of DUSP14 by which PRMT5-mediated arginine methylation may sequentially stimulate TRAF2-mediated DUSP14 ubiquitination and phosphatase activity, leading to inhibition of TCR signaling.—Yang, C.-Y., Chiu, L.-L., Chang, C.-C., Chuang, H.-C., Tan, T.-H. Induction of DUSP14 ubiquitination by PRMT5-mediated arginine methylation.

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Neolitsea acuminatissima (Lauraceae) is an endemic plant in Taiwan. One new carboline alkaloid, demethoxydaibucarboline A (1), two new eudesmanolide-type sesquiterpenes, methyl-neolitacumone A (2), neolitacumone E (3), and twelve known compounds (4–15) were isolated from the root of Neolitsea acuminatissima. Their structures were elucidated by spectroscopic analysis. Glucuronidation represents a major metabolism process of detoxification for carcinogens in the liver. However, intestinal bacterial β-Glucuronidase (βG) has been considered pivotal to colorectal carcinogenesis. To develop specific bacterial-βG inhibitors with no effect on human βG, methanolic extract of roots of N. acuminatissima was selected to evaluate their anti-βG activity. Among the isolates, demethoxydaibucarboline A (1) and quercetin (8) showed a strong bacterial βG inhibitory effect with an inhibition ratio of about 80%. Methylneolitacumone A (2) and epicatechin (10) exhibited a moderate or weak inhibitory effect and the enzyme activity was less than 45% and 74%, respectively. These four compounds specifically inhibit bacterial βG but not human βG. Thus, they are expected to be used for the purpose of reducing chemotherapy-induced diarrhea (CID). The results suggest that the constituents of N. acuminatissima have the potential to be used as CID relief candidates. However, further investigation is required to determine their mechanisms of action.