Regulation Of Leukemia-associated Rho GEF (LARG/ARHGEF12) Through Phosphorylation At S1288
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2022
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University of Hawaii at Manoa
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Leukemia-associated RhoGEF (LARG) is a guanine nucleotide exchange factor (GEF) that is selective for RhoA. High protein expression of LARG has been correlated with increased migration and invasion in cancer cells. LARG regulates migration, cell proliferation, invasion, and metastasis through its capacity to catalyze the exchange of GDP for GTP on RhoA, thereby triggering RhoA and its downstream pathways. The deletion of LARG has been shown to inhibit migration and invasion and increase chemotherapy sensitivity of GBM cells. Targeting LARG may have therapeutic potential for abrogating cancer invasion and for treating other LARG-dependent pathologies. A more detailed mechanistic understanding of LARG regulation is necessary in order to improve LARG targeting agents and to identify potential biomarkers and resistance mechanisms. Recently, LARG was found to be activated by phosphorylation at S1288 through active RSK2 and significantly increase the activation of RhoA. However, the mechanism by which this phosphorylation regulates LARG and increases the activation of RhoA was unknown. Here, the mechanism was defined by which phosphorylation at S1288 regulates LARG using biochemical and cell biological methods. This shows that LARG phosphorylation at S1288 significantly increases cell invasion and LARG’s ability to bind RhoA. Moreover, in response to EGF stimulation RSK2 phosphorylation of LARG at S1288 caused LARG trans-localization to the plasma membrane. Therefore, RSK2 drives cell motility through LARG phosphorylation at S1288 by inducing LARG membrane localization and promoting its binding with RhoA.Leukemia-associated RhoGEF (LARG) is a guanine nucleotide exchange factor (GEF) that is selective for RhoA. High protein expression of LARG has been correlated with increased migration and invasion in cancer cells. LARG regulates migration, cell proliferation, invasion, and metastasis through its capacity to catalyze the exchange of GDP for GTP on RhoA, thereby triggering RhoA and its downstream pathways. The deletion of LARG has been shown to inhibit migration and invasion and increase chemotherapy sensitivity of GBM cells. Targeting LARG may have therapeutic potential for abrogating cancer invasion and for treating other LARG-dependent pathologies. A more detailed mechanistic understanding of LARG regulation is necessary in order to improve LARG targeting agents and to identify potential biomarkers and resistance mechanisms. Recently, LARG was found to be activated by phosphorylation at S1288 through active RSK2 and significantly increase the activation of RhoA. However, the mechanism by which this phosphorylation regulates LARG and increases the activation of RhoA was unknown. Here, the mechanism was defined by which phosphorylation at S1288 regulates LARG using biochemical and cell biological methods. This shows that LARG phosphorylation at S1288 significantly increases cell invasion and LARG’s ability to bind RhoA. Moreover, in response to EGF stimulation RSK2 phosphorylation of LARG at S1288 caused LARG trans-localization to the plasma membrane. Therefore, RSK2 drives cell motility through LARG phosphorylation at S1288 by inducing LARG membrane localization and promoting its binding with RhoA.
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G proteins, Cellular signal transduction, Leukemia--Pathogenesis
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