Abstract
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.
Highlights
More than 90% of human cancer–related death is associated with tumor metastasis [1, 2]
Because GLK overexpression is correlated with cancer recurrence of human non–small cell lung cancer (NSCLC) and hepatoma [34, 35], we characterized whether polymerase II (Pol II)-GLK Tg mice spontaneously develop lung cancer or liver cancer using IHC analysis
We studied whether GLK transgene induces lung cancer (EGFRdel-positive) metastasis to other organs in surfactant protein A (SPA)-EGFRdel;Pol II-GLK Tg mice
Summary
More than 90% of human cancer–related death is associated with tumor metastasis [1, 2]. Cancer cell migration contributes to tumor metastasis [3]. Understanding the fundamental mechanisms of cancer cell migration should help the development of novel therapeutic approaches for treating cancer metastasis. IQ motif–containing GTPase-activating protein 1 (IQGAP1) is a scaffold protein that promotes multiple aspects of cell migration [4]. IQGAP1 weakens cell–cell adhesion, induces cytoskeletal rearrangement, and degrades extracellular matrix [5,6,7]. Upon phosphorylation by PKC-e at Ser-1443, IQGAP1 undergoes a conformational change and becomes activated [8]. The Rho family GTPases Cdc and Rac directly
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
