Disease relevance of ARHGEF12

• Leukemia-associated Rho guanine nucleotide exchange factor (LARG) was originally identified as a fusion partner with mixed-lineage leukemia in a patient with acute myeloid leukemia [1].
• Using oligonucleotide small interfering RNAs that suppress specific RGS-rhoGEF expression, we show that thrombin receptor stimulation of rho is primarily mediated by LARG in HEK293T and PC-3 prostate cancer cell lines [2].
• These data demonstrate that LARG is the first functional Dbl protein mutated in cancer and indicate LARG-mediated activation of RhoA may play a role in the development of human leukemias [1].
• Hyaluronan-CD44 interaction with leukemia-associated RhoGEF and epidermal growth factor receptor promotes Rho/Ras co-activation, phospholipase C epsilon-Ca2+ signaling, and cytoskeleton modification in head and neck squamous cell carcinoma cells [3].
• The LARG DH/PH domains have been overexpressed in Escherichia coli as a TEV protease-cleavable fusion protein containing maltose-binding protein and a hexahistidine tag at the N- and C-termini, respectively [4].

High impact information on ARHGEF12

• It was also found that LARG is phosphorylated on tyrosine by Tec [5].
• Transcriptional orientation of both genes at 11q23 is from centromere to telomere, consistent with other data that suggest the MLL-LARG fusion resulted from an interstitial deletion rather than a balanced translocation [6].
• Thus, LARG represents an additional member of the GEF family and a novel MLL fusion partner in acute myeloid leukemia [6].
• Immunoprecipitation and immunoblot analyses indicate that CD44 and the LARG protein are expressed in HSC-3 cells and that these two proteins are physically associated as a complex [3].
• Because of its role in RhoA activation, the LARG gene was analyzed as a positional candidate gene for this linkage [7].

Biological context of ARHGEF12

• The tissue distribution analysis indicated that plexin-B1 was co-localized with KIAA0380 and LARG in various tissues [8].
• LARG is an essential component of a positive feedback module through interactions with Dia1 [9] which controls Rho-ROCK and myosin function for contractility and amoeboid cell movement [10] of cancer cells as well as leucocytes
• LARG is found along microtubule tracks and associates with the centrosome (MTOC) to regulate cell polarity of motile cells [11]
• The LARG gene maps to a region on chromosome 11q23-24 that shows genetic linkage to BMI and type 2 diabetes in Pima Indians [7].
• Transfection of the HSC-3 cells with LARG-PDZcDNA significantly reduces LARG association with CD44 and EGFR [3].
• This patient also had the MLL-LARG fusion gene [12].

Anatomical context of ARHGEF12

• Immunocytochemical analysis showed that LARG was recruited to plasma membrane by plexin-B1 [8].
• In the RMA/RMU group, patients with small tumour cell nuclei had a worse prognosis than patients with larg tumour cell nuclei (P = 0.046) [13].
• Involvement of IGF-1/LARG Signaling in the Differentiation of Neural Stem Cells into Oligodendrocytes [14].

Associations of ARHGEF12 with chemical compounds

• Thus, we conclude that LARG is a RhoA-specific guanine nucleotide exchange factor [1].
• Sequencing of the LARG gene and genotyping of variants identified several polymorphisms that were associated with in vivo rates of insulin-mediated glucose uptake, at both physiological and maximally stimulating insulin concentrations, among 322 nondiabetic Pima Indians who had undergone a hyperinsulinemic-euglycemic clamp [7].
• A Functional Tyr1306Cys Variant in LARG Is Associated With Increased Insulin Action in Vivo [7].
• Critical role of lysine 204 in switch I region of Galpha13 for regulation of p115RhoGEF and leukemia-associated RhoGEF [15].
• Based on the crystal structure of Galphai1 in complex with RGS4, we mutated the Galpha13 residue lysine 204 to alanine (Galpha13K204A) and characterized the effect of this mutation in its regulation of RGS-RhoGEFs p115 or LARG [15].

Physical interactions of ARHGEF12

• Herein we describe the atomic structures of the catalytic Dbl homology (DH) and pleckstrin homology (PH) domains of LARG alone and in complex with RhoA [16].

Other interactions of ARHGEF12

• Leukemia-associated RhoGEF (LARG) belongs to a small subfamily of RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins [16].
• Indeed, we observed that PDZ-RhoGEF and LARG can form homo- and hetero-oligomers, whereas p115RhoGEF can only homo-oligomerize, and that this intermolecular interaction was mediated by their unique C-terminal regions [17].
• Together, these findings suggest the existence of a novel mechanism controlling the activity of PDZ-RhoGEF, LARG, and p115RhoGEF, which involves homo- and hetero-oligomerization through their inhibitory C-terminal region [17].

References