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. 2022 Jan;13(1):196-204.
doi: 10.1080/21541248.2021.1951590. Epub 2021 Jul 25.

Regulation of Leukaemia Associated Rho GEF (LARG/ARHGEF12)

Neda Z Ghanem  1   2 , Michelle L Matter  1   2 , Joe W Ramos  1   2
Affiliations

Regulation of Leukaemia Associated Rho GEF (LARG/ARHGEF12)

Neda Z Ghanem et al. Small GTPases. 2022 Jan.

Abstract

The Ras homologous (Rho) protein family of GTPases (RhoA, RhoB and RhoC) are the members of the Ras superfamily and regulate cellular processes such as cell migration, proliferation, polarization, adhesion, gene transcription and cytoskeletal structure. Rho GTPases function as molecular switches that cycle between GTP-bound (active state) and GDP-bound (inactive state) forms. Leukaemia-associated RhoGEF (LARG) is a guanine nucleotide exchange factor (GEF) that activates RhoA subfamily GTPases by promoting the exchange of GDP for GTP. LARG is selective for RhoA subfamily GTPases and is an essential regulator of cell migration and invasion. Here, we describe the mechanisms by which LARG is regulated to facilitate the understanding of how LARG mediates functions like cell motility and to provide insight for better therapeutic targeting of these functions.

Keywords: ARHGEF12; GTPase; LARG; Rho; RhoGef; migration; signal transduction.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1.
Figure 1.
LARG and RhoA Downstream Effectors Mediating Cell Motility. ROCK, Rho-associated protein kinase, mDia, Diaphanous-related formin-1; LIMK, LIM kinases; MLC, Myosin Light Chain.
Figure 2.
Figure 2.
Domain structure of LARG and its regulation. Phosphorylation and sequences important for the regulation of LARG activation and localization are indicated. NLS, nuclear localization signal; PDZ, post-synaptic density 95; disk large, zona occludens-1; RH, RGS homology; DH, Dbl homology; PH, Pleckstrin homology; CC, coiled-coil domain.
Figure 3.
Figure 3.
LARG activation and regulation. primary pathways of LARG activation in cell migration and invasion are depicted. Upon GPCR, EGFR/integrin binding to cognate ligands LARG can be activated by either Gα proteins or ERK/RSK respectively. Not shown are undefined tyrosine phosphorylations in the c-terminus that can also mediate activation via FAK or Fyn kinases. Dia1 can alternatively activate LARG GEF activity by binding to the coiled-coil region.
Figure 4.
Figure 4.
LARG Physiological Function. Depicted are known physiological functions of LARG/ARHGEF12 and potential therapeutic value of targeting LARG in each.
See this image and copyright information in PMC

References

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