The RhoGEF domain of p210 Bcr-Abl activates RhoA and is required for transformation

• Published in: Oncogene Vol. 27; no. 14; pp. 2064 - 2071
• Main Authors: Sahay, S, Pannucci, N L, Mahon, G M, Rodriguez, P L, Megjugorac, N J, Kostenko, E V, Ozer, H L, Whitehead, I P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.03.2008; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Apoptosis; BCR-ABL protein; Biological and medical sciences; cdc42 GTP-Binding Protein - metabolism; Cell Biology; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cellular proteins; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Fusion protein; Fusion Proteins, bcr-abl - chemistry; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Genetic transformation; Genetics; Guanine; Guanine nucleotide exchange factor; Guanine Nucleotide Exchange Factors - chemistry; Hematologic and hematopoietic diseases; Human Genetics; Humans; Internal Medicine; Kinases; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Mice; Molecular and cellular biology; Molecular biology; Mutants; Mutation; Myeloid cells; Myeloid Cells - metabolism; Oncogenes; Oncology; original-article; Phenotypes; Physiological aspects; Point Mutation; Protein kinases; Protein Structure, Tertiary - genetics; Protein-tyrosine kinase; Proteins; Proto-Oncogene Proteins c-bcr - chemistry; Proto-Oncogene Proteins c-bcr - genetics; Proto-Oncogene Proteins c-bcr - metabolism; Rho Guanine Nucleotide Exchange Factors; rhoA GTP-Binding Protein - metabolism; RhoA protein; United States; chronic myelogenous leukemia; p210 Bcr-Abl; transformation; RhoA; RhoGEF domain; Enzyme; Triphosphoric monoester hydrolases; Chronic myelogenous leukemia; dGTPase; Esterases; Malignant hemopathy; Carcinogenesis; Myeloproliferative syndrome; Hydrolases; Cancer
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/sj.onc.1210841

The BCR-ABL oncogene encodes an in-frame fusion protein containing N-terminal sequences derived from Bcr and C-terminal sequences derived from Abl. Bcr contains a centrally located Rho-specific guanine nucleotide exchange factor (RhoGEF) domain that is retained within p210 Bcr-Abl. Although this domain is subject to autoinhibition in the context of Bcr, here we show that it is constitutively activated in p210 Bcr-Abl. p210 Bcr-Abl can stimulate RhoA activation independently of its tyrosine kinase activity, and mutations within the RhoGEF domain that are predicted to eliminate RhoGEF activity inhibit RhoA activation. The RhoGEF mutant of p210 Bcr-Abl does not affect the tyrosine kinase activity of the molecule, nor the ability of p210 Bcr-Abl to interact with XPB through the RhoGEF domain. Despite retaining normal levels of tyrosine kinase activity, the RhoGEF mutant of p210 Bcr-Abl is impaired in transforming activity as measured by anchorage-independent growth. However, the mutant is still able to confer the phenotype of growth factor independence in myeloid cells, suggesting that some, but not all parameters of p210 Bcr-Abl transformation, are dependent upon a catalytically active RhoGEF domain. Collectively, these observations identify a gain-of-function activity attributable to the RhoGEF domain of p210 Bcr-Abl that is required to support the transformed phenotype.