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Molecular and Cellular Biology, April 2005, p. 2607-2621, Vol. 25, No. 7
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.7.2607-2621.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Kinase Activation through Dimerization by Human SH2-B{dagger}

Masahiro Nishi,{ddagger} Eric D. Werner,{ddagger} Byung-Chul Oh,{ddagger} J. Daniel Frantz, Sirano Dhe-Paganon, Lone Hansen, Jongsoon Lee, and Steven E. Shoelson*

Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts

Received 17 November 2004/ Accepted 21 December 2004

The isoforms of SH2-B, APS, and Lnk form a family of signaling proteins that have been described as activators, mediators, or inhibitors of cytokine and growth factor signaling. We now show that the three alternatively spliced isoforms of human SH2-B readily homodimerize in yeast two-hybrid and cellular transfections assays, and this is mediated specifically by a unique domain in its amino terminus. Consistent with previous reports, we further show that the SH2 domains of SH2-B and APS bind JAK2 at Tyr813. These findings suggested a model in which two molecules of SH2-B or APS homodimerize with their SH2 domains bound to two JAK2 molecules, creating heterotetrameric JAK2-(SH2-B)2-JAK2 or JAK2-(APS)2-JAK2 complexes. We further show that APS and SH2-B isoforms heterodimerize. At lower levels of SH2-B or APS expression, dimerization approximates two JAK2 molecules to induce transactivation. At higher relative concentrations of SH2-B or APS, kinase activation is blocked. SH2-B or APS homodimerization and SH2-B/APS heterodimerization thus provide direct mechanisms for activating and inhibiting JAK2 and other kinases from the inside of the cell and for potentiating or attenuating cytokine and growth factor receptor signaling when ligands are present.

* Corresponding author. Mailing address: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Phone: (617) 732-2528. Fax: (617) 735-1970. E-mail: steven.shoelson{at}joslin.harvard.edu.

{dagger} This study is dedicated to the memory of our friend and colleague, Valerie Fanikos.

{ddagger} M.N., E.D.W., and B.-C.O. contributed equally to this study.

Molecular and Cellular Biology, April 2005, p. 2607-2621, Vol. 25, No. 7
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.7.2607-2621.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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