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TGM1/3-mediated transamidation of Exo70 promotes tumor metastasis upon LKB1 inactivation

Published:27 August 2024 DOI: 10.1016/j.celrep.2024.114604 PMID: 39146185
Jihuan Hou,?Kunrong Mei,?Daxuan Wang,?Sunkui Ke,?Xiong Chen,?Jin Shang,?Guixia Li,?Yan Gao,?Huifang Xiong,?Haoran Zhang,?Lu Chen,?Wenqing Zhang,?Yabin Deng,?Xiaoting Hong,?Di-Ao Liu,?Tianhui Hu,?Wei Guo,?Yan-Yan Zhan

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.

Substances (6)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Cantharidin 56-25-7 C10H12O4 243 suppliers $34.50-$4000.00
Cantharidin 56-25-7 C10H12O4 243 suppliers $34.50-$4000.00
Norcantharidin 5442-12-6 C8H8O4 226 suppliers $16.00-$1602.00
Norcantharidin 5442-12-6 C8H8O4 226 suppliers $16.00-$1602.00
Norcantharidin 5442-12-6 C8H8O4 226 suppliers $16.00-$1602.00
Norcantharidin 5442-12-6 C8H8O4 226 suppliers $16.00-$1602.00

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