title: Constitutive Activity in an Ancestral Form of Abl Tyrosine Kinase.
abstract: The c-abl proto-oncogene encodes a nonreceptor tyrosine kinase that is found in all metazoans, and is ubiquitously expressed in mammalian tissues. The Abl tyrosine kinase plays important roles in the regulation of mammalian cell physiology. Abl-like kinases have been identified in the genomes of unicellular choanoflagellates, the closest relatives to the Metazoa, and in related unicellular organisms. Here, we have carried out the first characterization of a premetazoan Abl kinase, MbAbl2, from the choanoflagellate Monosiga brevicollis. The enzyme possesses SH3, SH2, and kinase domains in a similar arrangement to its mammalian counterparts, and is an active tyrosine kinase. MbAbl2 lacks the N-terminal myristoylation and cap sequences that are critical regulators of mammalian Abl kinase activity, and we show that MbAbl2 is constitutively active. When expressed in mammalian cells, MbAbl2 strongly phosphorylates cellular proteins on tyrosine, and transforms cells much more potently than mammalian Abl kinase. Thus, MbAbl2 appears to lack the autoinhibitory mechanism that tightly constrains the activity of mammalian Abl kinases, suggesting that this regulatory apparatus arose more recently in metazoan evolution.
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, 11794, United States of America.
authors.forename: Saadat U
authors.initials: SU
authors.lastname: Aleem
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, 11794, United States of America.
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Craddock
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, 11794, United States of America.
authors.forename: W Todd
authors.initials: WT
authors.lastname: Miller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D056897:Choanoflagellata / Q000201:enzymology / Q000235:genetics; D019143:Evolution, Molecular; D017125:Genes, Protozoan; D016313:Genes, abl; D057809:HEK293 Cells; D006801:Humans; D008322:Mammals / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D016315:Proto-Oncogene Proteins c-abl