Volume 272, Number 37, Issue of September 12, 1997 pp. 23231-23238
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

A Dominant Role of the Juxtamembrane Region of the TrkA Nerve Growth Factor Receptor during Neuronal Cell Differentiation

(Received for publication, April 17, 1997, and in revised form, July 2, 1997)

Sung Ok Yoon , Stephen P. Soltoff and Moses V. Chao

From the  Beth Israel Deaconess Medical Center, Division of Signal Transduction, Department of Medicine, Boston, Massachusetts 02115 and the Department of Cell Biology & Anatomy, Cornell University Medical College, New York, New York 10021

All receptor tyrosine kinases share a common intracellular signaling machinery, including ras activation, whereas cellular responses vary from mitogenesis to cell differentiation. To investigate the structural basis for receptor tyrosine kinase action for nerve growth factor, the juxtamembrane region of TrkA was transferred to a corresponding region of the epidermal growth factor (EGF) receptor. The resulting chimeric receptor contains an additional Shc site, Tyr⁴⁹⁰, in the juxtamembrane region. In transfected PC12 cell lines, neuronal differentiation was observed with EGF treatment, as evidenced by increased neurite extension. The action of the chimeric receptor was correlated with prolonged activation of MAP kinases and a 3-4-fold increase in phosphatidylinositol 3-kinase activity. The effect of the juxtamembrane chimera was dependent upon the Shc site at Tyr⁴⁹⁰, because expression of a chimeric receptor containing a Y490F mutation resulted in a complete loss of neuritogenesis by EGF treatment. These findings indicate that the juxtamembrane region of the TrkA receptor serves as a key functional domain that can confer a dominant effect upon neuronal differentiation.

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