Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease

• Published in: Oncogene Vol. 33; no. 31; pp. 4021 - 4035
• Main Authors: Cook, D R, Rossman, K L, Der, C J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.07.2014; Nature Publishing Group
• Subjects: 631/45/612/1232; 631/67; 692/420/755; Animals; Apoptosis; Cancer; Carcinogenesis; Cell Biology; Cell Division; Congenital Abnormalities - metabolism; Developmental disabilities; Disease; Enzymes; Epithelial cells; G proteins; Gene Expression Regulation, Neoplastic; Gene mutations; Genetic aspects; Genetic Diseases, Inborn - metabolism; Guanine; Guanine nucleotide exchange factor; Guanosine triphosphatases; Human Genetics; Humans; Identification and classification; Internal Medicine; Lymphocytes T; Medicine; Medicine & Public Health; Metastases; Neoplasms - metabolism; Oncology; Phosphatidylinositol; Proto-Oncogene Proteins c-vav - physiology; review; rho GTP-Binding Proteins - metabolism; Rho Guanine Nucleotide Exchange Factors - metabolism; Rodents; T-cell lymphoma; Tiam1 protein; mouse models; cancer; Rac1; guanine nucleotide exchange factors; RhoA; Cdc42
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.362

The aberrant activity of R as ho mologous (Rho) family small GTPases (20 human members) has been implicated in cancer and other human diseases. However, in contrast to the direct mutational activation of Ras found in cancer and developmental disorders, Rho GTPases are activated most commonly in disease by indirect mechanisms. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). RhoGEFs promote formation of the active GTP-bound state of Rho GTPases. The largest family of RhoGEFs is comprised of the Dbl family RhoGEFs with 70 human members. The multitude of RhoGEFs that activate a single Rho GTPase reflects the very specific role of each RhoGEF in controlling distinct signaling mechanisms involved in Rho activation. In this review, we summarize the role of Dbl RhoGEFs in development and disease, with a focus on Ect2 (epithelial cell transforming squence 2), Tiam1 ( T -cell lymphoma i nvasion and m etastasis 1 ), Vav and P-Rex1/2 (PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-triphosphate)-dependent R ac e x changer).