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Molecular and Cellular Biology, March 2001, p. 1613-1620, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1613-1620.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

SH2-B and APS Are Multimeric Adapters That Augment TrkA Signaling

Xiaozhong Qian and David D. Ginty*

Howard Hughes Medical Institute and the Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Received 14 June 2000/Returned for modification 27 July 2000/Accepted 28 November 2000

Neurotrophins influence growth and survival of sympathetic and sensory neurons through activation of their receptors, Trk receptor tyrosine kinases. Previously, we identified Src homology 2-B (SH2-B) and APS, which are structurally similar adapter proteins, as substrates of Trk kinases. In the present study, we demonstrate that both SH2-B and APS exist in cells as homopentamers and/or heteropentamers, independent of Trk receptor activation. Structure-function analyses revealed that the SH2-B multimerization domain resides within its amino terminus, which is necessary for SH2-B-mediated nerve growth factor (NGF) signaling. Overexpression of SH2-B enhances both the magnitude and duration of TrkA autophosphorylation following exposure of PC12 cells to NGF, and this effect requires the amino-terminal multimerization motif. Moreover, the amino terminus of SH2-B is necessary for TrkA/SH2-B-mediated morphological differentiation of PC12 cells. Together, these results indicate that the multimeric adapters SH2-B and APS influence neurotrophin signaling through direct modulation of Trk receptor autophosphorylation.

* Corresponding author. Mailing address: Howard Hughes Medical Institute and the Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205-2185. Phone: (410) 614-9494. Fax: (410) 614-8423. E-mail: dginty{at}jhmi.edu.

Molecular and Cellular Biology, March 2001, p. 1613-1620, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1613-1620.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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