HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 14, 13383-13392, April 2, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/14/13383    most recent M313356200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lai, K.-O. Articles by Ip, N. Y. Search for Related Content PubMed PubMed Citation Articles by Lai, K.-O. Articles by Ip, N. Y. Social Bookmarking                      What's this?

Identification of the Jak/Stat Proteins as Novel Downstream Targets of EphA4 Signaling in Muscle

IMPLICATIONS IN THE REGULATION OF ACETYLCHOLINESTERASE EXPRESSION^*

Kwok-On Lai, Yu Chen, Hoi-Man Po, Ka-Chun Lok, Ke Gong, and Nancy Y. Ip

From the Department of Biochemistry, Molecular Neuroscience Center and Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, People's Republic of China

Eph receptors and their cognate ligands ephrins are important players in axon guidance and neural patterning during development of the nervous system. Much of our knowledge about the signal transduction pathways triggered by Eph receptors has been related to the modulation of actin cytoskeleton, which is fundamental in mediating the cellular responses in growth cone navigation, cell adhesion, and cell migration. In contrast, little was known about whether long term activation of Eph receptor would regulate gene expression. Here we report a novel signaling pathway of EphA4, which involves activation of the tyrosine kinase Jak2 and the transcriptional activator Stat3. Transfection of COS7 cells with EphA4, but not the kinase-dead mutant, induced tyrosine phosphorylation of Jak2, Stat1, and Stat3. Treatment of cultured C2C12 myotubes with ephrin-A1 also induced tyrosine phosphorylation of Stat3, which was abolished by the Jak2 inhibitor AG490. Moreover, Jak2 was co-immunoprecipitated with EphA4 in muscle, and both proteins were concentrated at the neuromuscular junction (NMJ) of adult muscle. By using microarray analysis, we have identified acetylcholinesterase, the critical enzyme that hydrolyzed the neurotransmitter acetylcholine at the NMJ, as a downstream target gene of the Jak/Stat pathway in muscle. More importantly, ephrin-A1 increased the expression of acetylcholinesterase protein in C2C12 myotubes, which was abolished by AG490. In contrast, ephrin-A1 reduced the expression of fibronectin mRNA in C2C12 myotubes independently of Jak2. Finally, the expression level of acetylcholinesterase in limb muscle of EphA4 null mice was significantly reduced compared with the wild-type control. Taken together, these results have identified Jak/Stat proteins as the novel downstream targets of EphA4 signaling. In addition, the present study provides the first demonstration of a potential function of Eph receptors and Jak/Stat proteins at the NMJ.

Received for publication, December 8, 2003 , and in revised form, January 15, 2004.

^* This work was supported by the Research Grants Council of Hong Kong (HKUST 6103/00M, 6131/02M, and 2/99C) and the Area of Excellence Scheme of the University Grants Committee (AoE/B-15/01). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, People's Republic of China. Tel.: 852-2358-7304; Fax: 852-2358-2765; E-mail: BOIP{at}UST.HK.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Wykosky and W. Debinski The EphA2 Receptor and EphrinA1 Ligand in Solid Tumors: Function and Therapeutic Targeting Mol. Cancer Res., December 1, 2008; 6(12): 1795 - 1806. [Abstract] [Full Text] [PDF]

				J. J. Munoz, D. Alfaro, J. Garcia-Ceca, L. M. Alonso-C, E. Jimenez, and A. Zapata Thymic Alterations in EphA4-Deficient Mice J. Immunol., July 15, 2006; 177(2): 804 - 813. [Abstract] [Full Text] [PDF]

				Y. P. Ng, Z. H. Cheung, and N. Y. Ip STAT3 as a Downstream Mediator of Trk Signaling and Functions J. Biol. Chem., June 9, 2006; 281(23): 15636 - 15644. [Abstract] [Full Text] [PDF]

				Y. Liu, K. Cheng, K. Gong, A. K. Y. Fu, and N. Y. Ip Pctaire1 Phosphorylates N-Ethylmaleimide-sensitive Fusion Protein: IMPLICATIONS IN THE REGULATION OF ITS HEXAMERIZATION AND EXOCYTOSIS J. Biol. Chem., April 14, 2006; 281(15): 9852 - 9858. [Abstract] [Full Text] [PDF]

				S. Luo, Y. Chen, K.-O. Lai, J. C. Arevalo, S. C. Froehner, M. E. Adams, M. V. Chao, and N. Y. Ip {alpha}-Syntrophin regulates ARMS localization at the neuromuscular junction and enhances EphA4 signaling in an ARMS-dependent manner J. Cell Biol., June 6, 2005; 169(5): 813 - 824. [Abstract] [Full Text] [PDF]

				R. van Doorn, R. Dijkman, M. H. Vermeer, J. J. Out-Luiting, E. M. H. van der Raaij-Helmer, R. Willemze, and C. P. Tensen Aberrant Expression of the Tyrosine Kinase Receptor EphA4 and the Transcription Factor Twist in Sezary Syndrome Identified by Gene Expression Analysis Cancer Res., August 15, 2004; 64(16): 5578 - 5586. [Abstract] [Full Text] [PDF]