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TGM1/3-mediated transamidation of Exo70 promotes tumor metastasis upon LKB1 inactivation
Jihuan Hou1, Kunrong Mei2, Daxuan Wang3
1Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China.
Abstract:
Exo70, a key exocyst complex component, is crucial for cell motility and extracellular matrix (ECM) remodeling in cancer metastasis. Despite its potential as a drug target, Exo70's post-translational modifications (PTMs) are poorly characterized. Here, we report that Exo70 is transamidated on Gln5 with Lys56 of cystatin A by transglutaminases TGM1 and TGM3, promoting tumor metastasis. This modification enhances Exo70's association with other exocyst subunits, essential for secreting matrix metalloproteinases, forming invadopodia, and delivering integrins to the leading edge. Tumor suppressor liver kinase B1 (LKB1), whose inactivation accelerates metastasis, phosphorylates TGM1 and TGM3 at Thr386 and Thr282, respectively, to inhibit their interaction with Exo70 and the following transamidation. Cantharidin, a US Food and Drug Administration (FDA)-approved drug, inhibits Exo70 transamidation to restrain tumor cell migration and invasion. Together, our findings highlight Exo70 transamidation as a key molecular mechanism and target and propose cantharidin as a therapeutic strategy with direct clinical translational value for metastatic cancers, especially those with LKB1 loss.
Insights
Researchers discovered that Exo70 transamidation promotes cancer metastasis by enhancing exocyst complex function. Inhibiting this modification with cantharidin restrains tumor cell migration and invasion, offering a potential therapeutic strategy for metastatic cancers.
Area of Science:
- Cell Biology
- Cancer Research
- Biochemistry
Background:
- Exo70 is vital for cell motility and extracellular matrix remodeling in cancer metastasis.
- Post-translational modifications (PTMs) of Exo70 are not well understood, limiting its therapeutic potential.
Purpose of the Study:
- To investigate the post-translational modifications of Exo70.
- To elucidate the role of Exo70 modification in cancer metastasis.
- To identify potential therapeutic strategies targeting Exo70 modification.
Main Methods:
- Identified transamidation of Exo70 by transglutaminases TGM1 and TGM3.
- Investigated the role of liver kinase B1 (LKB1) in regulating Exo70 transamidation.
- Assessed the efficacy of cantharidin in inhibiting Exo70 transamidation and restraining tumor cell migration.
Main Results:
- Exo70 is transamidated with cystatin A by TGM1 and TGM3, promoting metastasis.
- LKB1 phosphorylates TGM1 and TGM3, inhibiting Exo70 transamidation.
- Cantharidin effectively inhibits Exo70 transamidation, reducing tumor cell migration and invasion.
Conclusions:
- Exo70 transamidation is a critical mechanism driving tumor metastasis.
- LKB1 inactivation accelerates metastasis by promoting Exo70 transamidation.
- Cantharidin represents a promising therapeutic agent for metastatic cancers, particularly those with LKB1 loss.
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