Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 28 May 2013
Vol. 6, Issue 277, p. ra40
[DOI: 10.1126/scisignal.2003936]

RESEARCH ARTICLES

Tyrosine Kinase BMX Phosphorylates Phosphotyrosine-Primed Motif Mediating the Activation of Multiple Receptor Tyrosine Kinases

Sen Chen1*, Xinnong Jiang1*{dagger}, Christina A. Gewinner2*{ddagger}, John M. Asara2, Nicholas I. Simon1, Changmeng Cai1, Lewis C. Cantley2,3, and Steven P. Balk1§

1 Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
2 Signal Transduction Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
3 Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065, USA.

* These authors contributed equally to this work.

{dagger} Present address: College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.

{ddagger} Present address: Research Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6BT, UK.

Abstract: The nonreceptor tyrosine kinase BMX (bone marrow tyrosine kinase gene on chromosome X) is abundant in various cell types and activated downstream of phosphatidylinositol-3 kinase (PI3K) and the kinase Src, but its substrates are unknown. Positional scanning peptide library screening revealed a marked preference for a priming phosphorylated tyrosine (pY) in the –1 position, indicating that BMX substrates may include multiple tyrosine kinases that are fully activated by pYpY sites in the kinase domain. BMX phosphorylated focal adhesion kinase (FAK) at Tyr577 subsequent to its Src-mediated phosphorylation at Tyr576. Loss of BMX by RNA interference or by genetic deletion in mouse embryonic fibroblasts (MEFs) markedly impaired FAK activity. Phosphorylation of the insulin receptor in the kinase domain at Tyr1189 and Tyr1190, as well as Tyr1185, and downstream phosphorylation of the kinase AKT at Thr308 were similarly impaired by BMX deficiency. However, insulin-induced phosphorylation of AKT at Ser473 was not impaired in Bmx knockout MEFs or liver tissue from Bmx knockout mice, which also showed increased insulin-stimulated glucose uptake, possibly because of decreased abundance of the phosphatase PHLPP (PH domain leucine-rich repeat protein phosphatase). Thus, by identifying the pYpY motif as a substrate for BMX, our findings suggest that BMX functions as a central regulator among multiple signaling pathways mediated by tyrosine kinases.

§ Corresponding author. E-mail: sbalk{at}bidmc.harvard.edu

Citation: S. Chen, X. Jiang, C. A. Gewinner, J. M. Asara, N. I. Simon, C. Cai, L. C. Cantley, S. P. Balk, Tyrosine Kinase BMX Phosphorylates Phosphotyrosine-Primed Motif Mediating the Activation of Multiple Receptor Tyrosine Kinases. Sci. Signal. 6, ra40 (2013).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Rapid Induction of Androgen Receptor Splice Variants by Androgen Deprivation in Prostate Cancer.
Z. Yu, S. Chen, A. G. Sowalsky, O. S. Voznesensky, E. A. Mostaghel, P. S. Nelson, C. Cai, and S. P. Balk (2014)
Clin. Cancer Res. 20, 1590-1600
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 28 May 2013.
S. P. Balk and A. M. VanHook (2013)
Science Signaling 6, pc14
   Abstract »    Full Text »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882