Disease relevance of ARHGAP26

• The SH3 domains of Graf and Graf2 purified from Escherichia coli bound directly to PKNbeta [1].
• The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q [2].
• The particular position of the human GRAF gene at 5q31 and the proposed antiproliferative and tumor suppressor properties of its avian homologue suggest that it also might be pathogenetically relevant for hematologic malignancies with deletions of 5q [2].
• Here, we report a second case--an infant acute monocytic leukemia (AML M5b)--with an MLL/GRAF fusion [3].
• Use of MLL/GRAF fusion mRNA for measurement of minimal residual disease during chemotherapy in an infant with acute monoblastic leukemia (AML-M5) [4].

Psychiatry related information on ARHGAP26

• Graf and D. L. Schacter (1985, Journal of Experimental Psychology: Learning, Memory and Cognition, 11, 501-518) [5].
• Contrary to the theory of the homeostatic model of self-concept, i.e., the expectancy that engaging in anti-social or pro-social behavior results typically in shifts in the self-concept (Graf, 1968; Deitz, 1970 shifts did not occur [6].

High impact information on ARHGAP26

• On the protein level, it is 90% homologous to the recently described chicken GRAF gene that functions as a GAP of RhoA in vivo and is thus a critical component of the integrin signaling transduction pathway [2].
• We have isolated the human GRAF gene (for GTPase regulator associated with the focal adhesion kinase pp125(FAK)) [2].
• We found point mutations within the GAP domain of the second GRAF allele in one patient [2].
• GRAF encodes a member of the Rho family of the GTPase-activating protein (GAP) family [2].
• In two additional patients we found an insertion of 52 or 74 bp within the GRAF cDNA that generates a reading frame shift followed by a premature stop codon [2].

Biological context of ARHGAP26

• Based on these data we suggest that phosphorylation of Graf by MAP kinase or related kinases may be a mechanism by which growth factor signaling modulates Rho-mediated cytoskeletal changes in PC12 and perhaps other cells [7].
• We examined the expression and regulation of Graf as a prelude to understanding the role of Graf in mediating signal transduction in vivo [7].
• Microinjection of Graf cDNA into subconfluent Swiss 3T3 cells (in the presence of serum) has marked effects on cell shape and actin localization [8].
• The Graf response was dependent on GAP activity, since injection of Graf cDNA containing point mutations in the GAP domain (R236Q or N351V) which block enzymatic activity, does not confer this phenotype [8].
• In a 1981 study by Graf et al, glycemic control and motor and sensory nerve conduction velocities were evaluated in 18 patients with non-insulin-dependent diabetes before and after one, three, six, and 12 months of antihyperglycemic therapy [9].

Anatomical context of ARHGAP26

• Graf expression causes clearing of stress fibers followed by formation of long actin based filopodial-like extensions [8].
• To further substantiate these results we examined the effect of Graf over-expression on Rho-mediated neurite retraction in nerve growth factor (NGF)-differentiated PC12 cells [8].
• The suppressed GRAF expression could be restored in leukaemia cell lines by treatment with a demethylating agent and an inhibitor of histone deacetylases [10].
• In contrast to normal tissues, which tested negative for GRAF promoter methylation, 11 of 29 (38%) bone marrow samples from patients with acute myeloid leukaemia or myelodysplastic syndrome were positive [10].
• Graf ligamentoplasty stabilizes the unstable segment through coaptation of bilateral facet joints [11].

Associations of ARHGAP26 with chemical compounds

• We suggest that Graf may function to mediate cross talk between the tyrosine kinases such as FAK and the Rho family GTPase that control steps in integrin-initiated signaling events [12].
• In addition, the mutation of serine 510 to alanine inhibited the epidermal growth factor-induced mobility shift of mutant Graf protein in vivo, consistent with serine 510 being the site of in vivo phosphorylation [7].
• 1. The ability of myo-inositol polyphosphates to inhibit iron-catalysed hydroxyl radical formation was studied in a hypoxanthine/xanthine oxidase system [Graf, Empson and Eaton (1987) J. Biol. Chem. 262, 11647-11650] [13].
• These effects of mucidin and strobilurin A are, however, qualitatively identical with those of myxothiazol, an antibiotic that inhibits respiration by binding to cytochrome b [Von Jagow, G., Ljungdahl, P. O., Graf, P., Ohnishi, T., & Trumpower, B. L. (1984) J. Biol. Chem. 259, 6319-6326] [14].
• Such feedings may have been essential for producing the previous observation (Graf, Balsam, & Silver, 1985) that pecking develops normally if squab which have been separated from their parents are given a daily 20-min interaction with seed followed by an immediate return to their parents [15].

Other interactions of ARHGAP26

• The full length of Graf2 contains a putative PH domain, a RhoGAP domain, and an SH3 domain as well as Graf [1].

Analytical, diagnostic and therapeutic context of ARHGAP26

• Reverse-transcriptase polymerase chain reaction (PCR) showed that exon 9 of MLL was fused in-frame with exon 19 of GRAF [3].
• Extralong genomic PCR with subsequent sequence analysis demonstrated that the breakpoints occurred in intron 9 of MLL, nine base pairs (bp) downstream from exon 9, and in intron 18 of GRAF, 117 bp downstream from exon 18 [3].
• However, Southern blot and fluorescence in situ hybridization analyses revealed that MLL was rearranged and that the 5' part of the MLL gene was inserted into 5q in the vicinity of 5q31, which harbors GRAF [3].
• CONCLUSIONS: Graf ligamentoplasty cannot completely replace spinal fusion [16].
• The kappa values for interobserver variability indicated moderate agreement (kappa 0.47) for the exact Graf classification and substantial agreement (kappa 0.65) for the classification of normal (type I) versus abnormal (type IIa-IV) [17].

References