Current Biology
Volume 8, Issue 15, 16 July 1998, Pages 856-863
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Research Paper
Identification of a signal sequence necessary for the unconventional secretion of Engrailed homeoprotein

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Abstract

Background: Engrailed-1 and Engrailed-2 are homeoproteins – transcription factors implicated in the morphogenesis of discrete structures. Engrailed proteins have a role in patterning the midbrain–hindbrain region and are expressed in the nuclei of rat embryo midbrain–hindbrain cells. We have previously found that both endogenous and exogenously expressed Engrailed proteins also associate with membrane regions implicated in signal transduction and secretion. Within total membrane fractions, a small proportion of Engrailed – about 5% – is protected against proteinase K proteolysis, suggesting that Engrailed has access to a luminal compartment. Together with our finding that homeodomains and homeoproteins can be internalized by live cells, these observations suggest that Engrailed might act as a polypeptidic messenger. In order to investigate this possibility, we looked to see if Engrailed could be secreted.

Results: Engrailed expressed in COS cells can be recovered in abutting primary neurons and this is dependent on a short sequence in its homeodomain distinct from ‘classical’ secretion signals. This sequence, which overlaps with the sequence necessary for Engrailed internalization and which is highly conserved among homeoproteins, is the first example of an ‘unconventional’ sequence necessary for secretion. Less than 5% of total intracellular Engrailed is secreted and there is a correlation between secretion and access to the membrane compartment where the protein is protected against proteinase K.

Conclusions: Our results lend weight to the proposal that Engrailed, and possibly other homeoproteins, might act as intercellular polypeptidic messengers.

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A Joliot, A Maizel, D Rosenberg, A Trembleau, S Dupas and A Prochiantz, CNRS URA 1414, Ecole Normale Supérieure, 46, rue d’Ulm, 75230 Cedex Paris 05, France.

M Volovitch, CNRS URA 1414, Ecole Normale Supérieure, 46, rue d’Ulm, 75230 Cedex Paris 05 and Université Paris 7, UFR de Biologie, 2 Place Jussieu, 75005 France.

E-mail address for A Prochiantz (corresponding author): [email protected].