Disease relevance of ARHGEF11

• In neuroblastoma Neuro2a cells, KIAA0380 was observed in the tips of neurites, a location where cortical actin reorganization is induced upon stimulation with lysophosphatidic acid [1].
• METHODS: For the current report, the authors studied the risk of lung cancer associated with a nonsynonymous SNP (rs868188; Ser1416Gly) in PDZ-RhoGEF in a large lung cancer case-control study of 2260 Caucasians and 369 Mexican Americans [2].

High impact information on ARHGEF11

• Here we report the identification and characterization of two proteins, GTRAP41 and GTRAP48 (for glutamate transporter EAAT4 associated protein) that specifically interact with the intracellular carboxy-terminal domain of EAAT4 and modulate its glutamate transport activity [3].
• In addition, a dominant-negative form of PDZ-RhoGEF blocks semaphorin 4D-induced growth cone collapse in primary hippocampal neurons [4].
• This interaction results in the phosphorylation of PDZ RhoGEF and abolishes its ability to mediate the accumulation of Rho-GTP by Galpha13 [5].
• Identification of a novel sequence in PDZ-RhoGEF that mediates interaction with the actin cytoskeleton [6].
• Extensive deletion mutagenesis revealed the presence of a novel 25-amino acid sequence in PDZ-RhoGEF, located at amino acids 561-585, that is necessary and sufficient for localization to the actin cytoskeleton and interaction with actin [6].

Anatomical context of ARHGEF11

• Expression of ARHGEF11 mRNA in schizophrenic thalamus [7].
• Molecular dissection analyses revealed that a proline-rich motif C-terminally adjacent to DH/PH domain is essential for plasma membrane localization of KIAA0380 and cortical actin reorganization followed by cell rounding [1].
• When expressed in J82 cells, DH/PH domain-containing forms of KIAA0380 induced actin stress fibers, whereas expression of the RGS homology domain prevented lysophosphatidic acid (LPA)-induced stress fiber formation [8].

Associations of ARHGEF11 with chemical compounds

• Functions of a rho-specific guanine nucleotide exchange factor in neurite retraction. Possible role of a proline-rich motif of KIAA0380 in localization [1].
• Disruption of the cortical actin cytoskeleton in cells by using latrunculin B prevents the peri-plasma membrane localization of PDZ-RhoGEF [6].
• Rho-specific binding and guanine nucleotide exchange catalysis by KIAA0380, a dbl family member [8].
• Also, VSMCs express PDZ-Rho guanine nucleotide exchange factor (GEF) and Ang II stimulated PYK2 association with tyrosine phosphorylated PDZ-RhoGEF [9].

Other interactions of ARHGEF11

• These include the direct association of their RGS domain with GTP-bound forms of Galpha(12/13) and the binding of the PDZ domain present in PDZ-RhoGEF and LARG to plexins, which are receptors for semaphorins [10].
• In contrast, GTRAP48, a homolog of p115 RhoGEF, bound to Galpha(13) but was not stimulated by the alpha subunit and had very poor GAP activity [11].
• Preliminary crystallographic analysis of the complex of the human GTPase RhoA with the DH/PH tandem of PDZ-RhoGEF [12].
• This report demonstrates that PDZ-RhoGEF, a member of a subfamily of RhoGEFs that contain regulator of G protein signaling domains, is partially localized at or near the plasma membranes in 293T, COS-7, and Neuro2a cells, and this localization is coincident with cortical actin [6].
• The results suggest that there are interactions between RGS2, RGS6, and PDZ-RhoGEF and validate this family of proteins as key regulators of tumorigenesis [2].

Analytical, diagnostic and therapeutic context of ARHGEF11

• CONCLUSIONS: To the authors' knowledge, this is the first epidemiological study to link PDZ-RhoGEF polymorphisms with cancer risk [2].

References