Disease relevance of Arhgef1

• Lsc-deficient neutrophils are recruited normally to sites of bacterial peritonitis and chemical dermatitis, indicating that other signaling pathways compensate for the Lsc deficiency in some forms of inflammation [1].
• Lsc-deficient mice have a peripheral leukocytosis and extramedullary hematopoiesis, demonstrating that Lsc is required for leukocyte homeostasis [1].
• We found that Lsc(-/-) mice on a BALB/c background show thymic hyperplasia due to increased numbers of thymocytes and that these numbers further increase with the age of the mice [2].
• Finally, PAR-1 transforming activity was blocked by pertussis toxin and by co-expression of the RGS domain of Lsc, implicating Galpha(i) and Galpha(12)/Galpha(13) subunits, respectively, as mediators of PAR-1 transformation [3].

High impact information on Arhgef1

• Lsc regulates marginal-zone B cell migration and adhesion and is required for the IgM T-dependent antibody response [4].
• These data demonstrate that Lsc regulates the migration and adhesion of MZB cells, and this regulation appears to be required for these cells to contribute to the antibody response to TD antigens [4].
• Lsc is essential for marginal zone B (MZB) cell homeostasis and for the generation of immune responses [5].
• Although Lsc-deficient lymphocytes show reduced basal motility, MZB cells show enhanced migration after serum activation [5].
• Lsc is expressed primarily in the hematopoietic system and links the activation of G alpha(12) and G alpha(13)-coupled receptors to actin polymerization in B and T cells [5].

Biological context of Arhgef1

• The transforming cDNA encodes a truncated protein (designated Lsc) with a region of sequence similarity to the product of the lbc oncogene [6].
• The Lsc RhoGEF mediates signaling from thromboxane A2 to actin polymerization and apoptosis in thymocytes [2].
• Additionally, in the absence of Lsc, phosphorylation of the survival kinase Akt in response to TXA(2) was greatly enhanced [2].

Anatomical context of Arhgef1

• We have disrupted the Lsc gene and demonstrated that formyl-peptide-stimulated Lsc knock-out (KO) neutrophils are unable to generate and sustain a single-dominant pseudopod and migrate with increased speed and reduced directionality [1].
• Overexpression of Lfc in NIH 3T3 cells induced the formation of actin stress fibers and membrane ruffles, consistent with the activation of both RhoA and Rac1 signaling pathways, whereas overexpression of Lsc led exclusively to well developed stress fibers [7].
• Chondrocyte-derived ezrin-like domain containing protein (CDEP), a rho guanine nucleotide exchange factor, is inducible in chondrocytes by parathyroid hormone and cyclic AMP and has transforming activity in NIH3T3 cells [8].

Associations of Arhgef1 with chemical compounds

• Lfc and Lsc oncoproteins represent two new guanine nucleotide exchange factors for the Rho GTP-binding protein [9].

Physical interactions of Arhgef1

• Consistent with these results, Lbc, Lfc, and Lsc each form tight complexes with the guanine nucleotide-depleted form of Rho and bind weakly to the GDP- and GTPgammaS-bound states [9].

Other interactions of Arhgef1

• These results demonstrate that Lsc links formyl-peptide receptors to RhoA signaling pathways that regulate polarization, migration, and adhesion in neutrophils and that Lsc is required for leukocyte homeostasis [1].
• Unexpectedly, we also found that Lsc is required for normal beta2- and beta1-integrin-dependent neutrophil adhesion [1].

References