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γ-Secretase Cleavage and Nuclear Localization of ErbB-4 Receptor Tyrosine Kinase

Chang-Yuan Ni, M. Paul Murphy, Todd E. Golde and Graham Carpenter
Science
New Series, Vol. 294, No. 5549 (Dec. 7, 2001), pp. 2179-2181
Stable URL: http://www.jstor.org/stable/3085364
Page Count: 3
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Abstract

ErbB-4 is a transmembrane receptor tyrosine kinase that regulates cell proliferation and differentiation. After binding of its ligand heregulin (HRG) or activation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA), the ErbB-4 ectodomain is cleaved by a metalloprotease. We now report a subsequent cleavage by γ-secretase that releases the ErbB-4 intracellular domain from the membrane and facilitates its translocation to the nucleus. γ-Secretase cleavage was prevented by chemical inhibitors or a dominant negative presenilin. Inhibition of γ-secretase also prevented growth inhibition by HRG. γ-Secretase cleavage of ErbB-4 may represent another mechanism for receptor tyrosine kinase-mediated signaling.

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