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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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