title: A secreted tyrosine kinase acts in the extracellular environment.
abstract: Although tyrosine phosphorylation of extracellular proteins has been reported to occur extensively in vivo, no secreted protein tyrosine kinase has been identified. As a result, investigation of the potential role of extracellular tyrosine phosphorylation in physiological and pathological tissue regulation has not been possible. Here, we show that VLK, a putative protein kinase previously shown to be essential in embryonic development, is a secreted protein kinase, with preference for tyrosine, that phosphorylates a broad range of secreted and ER-resident substrate proteins. We find that VLK is rapidly and quantitatively secreted from platelets in response to stimuli and can tyrosine phosphorylate coreleased proteins utilizing endogenous as well as exogenous ATP sources. We propose that discovery of VLK activity provides an explanation for the extensive and conserved pattern of extracellular tyrosine phosphophorylation seen in vivo, and extends the importance of regulated tyrosine phosphorylation into the extracellular environment.
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Mattia R
authors.initials: MR
authors.lastname: Bordoli
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA; Department of Life Science and Global Top5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Jina
authors.initials: J
authors.lastname: Yum
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Susanne B
authors.initials: SB
authors.lastname: Breitkopf
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Thon
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Vascular Biology Program, Department of Surgery, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Italiano
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92031, USA.
authors.forename: Junyu
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92031, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Worby
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Swee-Kee
authors.initials: SK
authors.lastname: Wong
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Lin
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Maja
authors.initials: M
authors.lastname: Edenius
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Keller
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92031, USA.
authors.forename: Jack E
authors.initials: JE
authors.lastname: Dixon
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA; Department of Life Science and Global Top5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: cyeo@ewha.ac.kr.
authors.forename: Chang-Yeol
authors.initials: CY
authors.lastname: Yeo
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA. Electronic address: mwhitman@hms.harvard.edu.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Whitman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D004622:Embryo, Mammalian / Q000201:enzymology*; D047108:Embryonic Development; D006031:Glycosylation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D055571:Secretory Pathway
chemical_list: D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C543966:Vlk protein, mouse; C000594807:PKDCC protein, human