NDLI: Leukemia-associated Rho Guanine Nucleotide Exchange Factor, a Dbl Family Protein Found Mutated in Leukemia, Causes Transformation by Activation of RhoA

Content Provider	Journal of Biological Chemistry (JBC)
Author	Reuther, Gary W. Lambert, Que T. Booden, Michelle A. Wennerberg, Krister Becknell, Brian Marcucci, Guido Sondek, John Caligiuri, Michael A. Der, Channing J.
Abstract	Leukemia-associated Rho guanine nucleotide exchange factor (LARG) was originally identified as a fusion partner with mixed-lineage leukemia in a patient with acute myeloid leukemia. LARG possesses a tandem Dbl homology and pleckstrin homology domain structure and, consequently, may function as an activator of Rho GTPases. In this study, we demonstrate that LARG is a functional Dbl protein. Expression of LARG in cells caused activation of the serum response factor, a known downstream target of Rho-mediated signaling pathways. Transient overexpression of LARG did not activate the extracellular signal-regulated kinase or c-Jun NH2-terminal kinase mitogen-activated protein kinase cascade, suggesting LARG is not an activator of Ras, Rac, or Cdc42. We performed in vitro exchange assays where the isolated Dbl homology (DH) or DH/pleckstrin homology domains of LARG functioned as a strong activator of RhoA, but exhibited no activity toward Rac1 or Cdc42. We found that LARG could complex with RhoA, but not Rac or Cdc42, in vitro, and that expression of LARG caused an increase in the levels of the activated GTP-bound form of RhoA, but not Rac1 or Cdc42, in vivo. Thus, we conclude that LARG is a RhoA-specific guanine nucleotide exchange factor. Finally, like activated RhoA, we determined that LARG cooperated with activated Raf-1 to transform NIH3T3 cells. These data demonstrate that LARG is the first functional Dbl protein mutated in cancer and indicate LARG-mediated activation of RhoA may play a role in the development of human leukemias.
Related Links	http://www.jbc.org/content/276/29/27145.abstract
Ending Page	27151
Starting Page	27145
Page Count	7
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	29
Volume Number	276
DOI	10.1074/jbc.M103565200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2001-07-20
Access Restriction	Open
Subject Keyword	Guanine nucleotide exchange factor (GEF) Dbl homology (DH) Pleckstrin homology (PH) Leukemia-associated Rho guanine nucleotide exchange factor (LARG) Mixed-lineage leukemia (MLL) Regulator of G protein signaling (RGS) Acute myeloid leukemia (AML) Jun NH2-terminal kinase (JNK) Serum response factor (SRF) Glutathione S-transferase (GST) G protein-coupled receptor (GPCR) Polymerase chain reaction (PCR) . hemagglutinin (HA) Wild type (WT) N-methylanthraniloyl (mant) Ras/Rho binding domain (RBD) MECHANISMS OF SIGNAL TRANSDUCTION
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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