Disease relevance of RASGRF2

• Aberrant methylation of RASGRF2 and RASSF1A in human non-small cell lung cancer [1].
• RASSF1A, regarded as a TSG, has been extensively studied in lung cancer and other malignant tumors, whereas RASGRF2 has only been reported to possibly play a role in the pathogenesis of pancreatic cancer cell lines [1].
• Loss of RASGRF2 expression was presented in 36% lung cancer cell lines while aberrant methylation of RASGRF2 was present in 30% (3/10) non-small cell lung cancer (NSCLC) cell lines and in 25% (1/4) small cell lung cancer (SCLC) cell lines [1].

High impact information on RASGRF2

• With the aid of H-Ras constructs specifically tethered to the plasma membrane, endoplasmic reticulum, and Golgi complex, we demonstrate that RasGRF1 and RasGRF2 can activate plasma membrane and reticular, but not Golgi-associated, H-Ras [2].
• Cdc42N17 was also found to inhibit the translocation of Ras-GRF2, a guanine nucleotide exchange factor for Ras and Rac but not for Cdc42 [3].
• GRF2 lacking the Cdc25 domain is not ubiquitinated, suggesting that a protein that cannot bind Ras cannot be properly targeted for destruction [4].
• Ras is a small GTPase that is activated by upstream guanine nucleotide exchange factors, one of which is Ras-GRF2 [4].
• Point mutations within the Cdc25 domain that eliminate Ras binding also eliminate ubiquitination, demonstrating that binding to Ras is necessary for ubiquitination of GRF2 [4].

Biological context of RASGRF2

• In this screen, a positive cDNA clone from a human brain cDNA library was isolated which consisted of the GRF2 DH domain and its adjacent ilimaquinone domain [5].
• The concordance between loss of expression and aberrant methylation of RASGRF2 was 86% (12/14) [1].
• We examined RASGRF2 expression by reverse transcription PCR and aberrant methylation of RASGRF2 by methylation-specific PCR in lung cancer cell lines [1].
• Analysis of chimeras between Ras-GRF1 and Ras-GRF2 demonstrated that a 30-amino acid segment embedded with their catalytic domains was responsible for recognizing the presence of different lipids on Ras proteins [6].

Anatomical context of RASGRF2

• Epithelial cells overexpressing Ras-GRF2 are morphologically transformed and grow in a disorganized manner with minimal intercellular contacts [7].
• RASGRF2 expression was restored after treatment with the demethylating agent, 5-aza-2'-deoxycytidine in all four cell lines tested that downregulated RASGRF2 expression [1].

Associations of RASGRF2 with chemical compounds

• Cloning and characterization of Ras-GRF2, a novel guanine nucleotide exchange factor for Ras [7].

Regulatory relationships of RASGRF2

• The exchange factor Ras-GRF2 activates Ras-dependent and Rac-dependent mitogen-activated protein kinase pathways [8].

Other interactions of RASGRF2

• The Ras-GRF1 and Ras-GRF2 proteins, which couple Ras activation to serpentine receptors and calcium signals, contain both Cdc25 and DbI homology (DH) regions [3-4] [8].
• Calmodulin-independent coordination of Ras and extracellular signal-regulated kinase activation by Ras-GRF2 [9].
• Frequent methylation and silencing of RASGRF2 in tumor cells may play an important role, different from that of RASSF1A, in the carcinogenesis of NSCLC [1].
• We report here that p35 associates with Ras guanine nucleotide releasing factor 2 (RasGRF2) in coimmunoprecipitation and colocalization studies using transfected cell lines as well as primary cortical neurons [10].

References