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J. Cell Biol.,
Volume 145, Number 7, June 28, 1999 1419-1433
MRC Laboratory for Molecular Cell Biology, and Department of Biochemistry and Molecular Biology, University College
London, London WC1E 6BT, United Kingdom
By analyzing the trafficking of HRP-P-selectin chimeras in which the lumenal domain of P-selectin
was replaced with horseradish peroxidase, we determined the sequences needed for targeting to synaptic-like microvesicles (SLMV), dense core granules
(DCG), and lysosomes in neuroendocrine PC12 cells.
Within the cytoplasmic domain of P-selectin, Tyr777 is
needed for the appearance of P-selectin in immature
and mature DCG, as well as for targeting to SLMV. The
latter destination also requires additional sequences
(Leu768 and 786DPSP789) which are responsible for
movement through endosomes en route to the SLMV.
Leu768 also mediates transfer from early transferrin (Trn)-positive endosomes to the lysosomes; i.e., operates as a lysosomal targeting signal. Furthermore,
SLMV targeting of HRP-P-selectin chimeras, but not
the endogenous SLMV protein synaptophysin/p38, previously shown to be delivered to SLMV directly from
the plasma membrane, is a Brefeldin A-sensitive process. Together, these data are consistent with a model of
SLMV biogenesis which involves an endosomal intermediate in PC12 cells. In addition, we have discovered
that impairment of SLMV or DCG targeting results in a concomitant increase in lysosomal delivery, illustrating the entwined relationships between routes leading
to regulated secretory organelles (RSO) and to lysosomes.
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