A secreted tyrosine kinase acts in the extracellular environment

Mattia R. Bordoli, Jina Yum, Susanne B. Breitkopf, Jonathan N. Thon, Joseph E. Italiano, Junyu Xiao, Carolyn Worby, Swee Kee Wong, Grace Lin, Maja Edenius, Tracy L. Keller, John M. Asara, Jack E. Dixon, Chang Yeol Yeo, Malcolm Whitman

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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. PaperClip

Original languageEnglish
Pages (from-to)1033-1044
Number of pages12
JournalCell
Volume158
Issue number5
DOIs
StatePublished - 28 Aug 2014

Bibliographical note

Funding Information:
The authors would like to thank Min Yuan for help with mass spectrometry experiments, Peter Hornbeck (Cell Signaling Technologies) for valuable discussions, Ross Okazaki and Rajesh Kulenthirarajan for platelet isolation, and Shin-Ichi Nishikawa (RIKEN) for cDNAs encoding wild-type mouse VLK and VLK KM . This work was supported in part by the National Institutes of Health grants GM089885 and DE024312 (M.W.), Hl68130 (J.E.I.), 1K99HL114719-01A1 (J.N.T), 5P30CA006516, 5P01CA120964, NIH shared instrumentation grant 1S10OD010612 (J.M.A.), DK 18024, and DK 18849 (J.E.D.), and grants from the Korean Government to C.Y.Y. (NRF 2012R1A5A1048236 and 2012R1A2A2A01046485, Next Generation BioGreen 21 Program PJ00812701). M.R.B. was supported by a Swiss National Science Foundation fellowship.

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