Tyrosine phosphorylation of Dbl regulates GTPase signaling.
Rho GTPases are molecular "switches" that cycle between "on" (GTP-bound) and "off" (GDP-bound) states and regulate numerous cellular activities such as gene expression, protein synthesis, cytoskeletal rearrangements, and metabolic responses. Dysregulation of GTPases is a key feature of many diseases, especially cancers. Guanine nucleotide exchange factors (GEFs) of the Dbl family are activated by mitogenic cell surface receptors and activate the Rho family GTPases Cdc42, Rac1, and RhoA. The molecular mechanisms that regulate GEFs from the Dbl family are poorly understood. Our studies reveal that Dbl is phosphorylated on tyrosine residues upon stimulation by growth factors and that this event is critical for the regulated activation of the GEF. These findings uncover a novel layer of complexity in the physiological regulation of this protein.
From the Departments of Pharmacology, and Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
Meghana
M
Gupta
Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
Xiaojun
X
Qi
Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
Varsha
V
Thakur
From the Departments of Pharmacology, and Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 dxm178@case.edu.
Danny
D
Manor
D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D036341:Intercellular Signaling Peptides and Proteins; D014443:Tyrosine; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
Guanine Nucleotide Exchange Factor (GEF); Phosphorylation; Phosphotyrosine; Rho GTPases; Small GTPase