The processing of ErbB-4 parallels that of AβPP and Notch, report Graham Carpenter at Vanderbilt University School of Medicine and colleagues elsewhere. Activation of ErbB-4 leads to its cleavage first by the metalloproteinase TACE, (which can also function as an α-secretase cleaving AβPP). That generates a 120 kDa extracellular domain and a membrane-bound 80 kDa fragment (m80) comprising the cytoplasmic and transmembrane domains. The authors show that small amounts of a second, soluble 80 kDa fragment (s80) are also formed.

Several lines of evidence support their contention that γ-secretase, not caspases or the proteasome, generates the soluble fragment. Caspase and proteasome inhibitors were unable to block the production of s80 upon ErbB-4 activation, whereas any of three different γ-secretase inhibitors abrogated s80 production. Furthermore, in cells treated with the ErbB-4 ligand TPA, expression of wildtype presenilin-1 (PS1) led to increased s80production, but s80 was undetectable when cells expressed a dominant-negative PS1 mutant.

γ-secretase may be directly involved in ErbB-4 signal transduction, as the γ-secretase inhibitor H5106 prevented the translocation of s80 to the nucleus. Equally worrisome, perhaps, is the researchers' finding that the ability of Erb4, mediated by its ligand heregulin, to stop proliferation and instead induce differentiation in breast cancer cells requires γ-secretase; the inhibitor Compound E completely extinguished this activity. "This is a fascinating paper. Scientifically it is very well done," said Christian Haass, Ludwig-Maximilians-University, Munich. "I think companies should be concerned about using γ-secretase inhibitors as drugs; they would need to be used for the long term and could potentially cause cancer."-Tom Fagan.

Reference:Ni CY, Murphy MP, Golde TE, Carpenter G. g-secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science. 2001 Dec 7;294(5549):2179-81. Abstract