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Cell. 2014 Aug 28;158(5):1033-1044. doi: 10.1016/j.cell.2014.06.048.

A secreted tyrosine kinase acts in the extracellular environment.

Author information

1
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
2
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.
3
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
5
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.
6
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92031, USA.
7
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.
8
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA. Electronic address: mwhitman@hms.harvard.edu.

Erratum in

  • Cell. 2014 Nov 6;159(4):955.

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.

Comment in

PMID:
25171405
PMCID:
PMC4149754
DOI:
10.1016/j.cell.2014.06.048
[Indexed for MEDLINE]
Free PMC Article

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