title: Novel autophosphorylation sites of Src family kinases regulate kinase activity and SH2 domain-binding capacity.
abstract: Src family tyrosine kinases (SFKs) are critical players in normal and aberrant biological processes. While phosphorylation importantly regulates SFKs at two known tyrosines, large-scale phosphoproteomics have revealed four additional tyrosines commonly phosphorylated in SFKs. We found these novel tyrosines to be autophosphorylation sites. Mimicking phosphorylation at the C-terminal site to the activation loop decreased Fyn activity. Phosphomimetics and direct phosphorylation at the three SH2 domain sites increased Fyn activity while reducing phosphotyrosine-dependent interactions. While 68% of human SH2 domains exhibit conservation of at least one of these tyrosines, few have been found phosphorylated except when found in cis to a kinase domain.
authors.affiliation: Department of Biology, University of Vermont, Burlington, VT, USA.
authors.forename: Marion E
authors.initials: ME
authors.lastname: Weir
authors.affiliation: Department of Medical Laboratory and Radiation Sciences, University of Vermont, Burlington, VT, USA.
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Mann
authors.affiliation: Otto-Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Corwin
authors.affiliation: Department of Biology, University of Vermont, Burlington, VT, USA.|Department of Biology and Physical Education, Norwich University, Northfield, VT, USA.
authors.forename: Zachary W
authors.initials: ZW
authors.lastname: Fulton
authors.affiliation: Department of Biology, University of Vermont, Burlington, VT, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Hao
authors.affiliation: Department of Biology, University of Vermont, Burlington, VT, USA.
authors.forename: Jeanine F
authors.initials: JF
authors.lastname: Maniscalco
authors.affiliation: Department of Biology, University of Vermont, Burlington, VT, USA.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Kenney
authors.affiliation: Department of Biology, University of Vermont, Burlington, VT, USA.
authors.forename: Kristal M
authors.initials: KM
authors.lastname: Roman Roque
authors.affiliation: Department of Biology, University of Vermont, Burlington, VT, USA.|Department of Biology and Physical Education, Norwich University, Northfield, VT, USA.
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Chapdelaine
authors.affiliation: Otto-Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Stelzl
authors.affiliation: Department of Medical Laboratory and Radiation Sciences, University of Vermont, Burlington, VT, USA.
authors.forename: Paula B
authors.initials: PB
authors.lastname: Deming
authors.affiliation: Department of Biology, University of Vermont, Burlington, VT, USA.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Ballif
authors.affiliation: Department of Biology, University of Vermont, Burlington, VT, USA.|Department of Biology and Physical Education, Norwich University, Northfield, VT, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Hinkle
mesh_terms: D000596:Amino Acids / Q000235:genetics; D017124:Conserved Sequence; D057809:HEK293 Cells; D006801:Humans; D013058:Mass Spectrometry; D010766:Phosphorylation; D019000:Phosphotyrosine; D011485:Protein Binding; D051076:Proto-Oncogene Proteins c-fyn / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013329:Structure-Activity Relationship; D018909:src Homology Domains; D019061:src-Family Kinases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D019000:Phosphotyrosine; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases
keywords: Src family kinase; mass spectrometry; phosphorylation