Signaling from the Secretory Granule to the Nucleus: Uhmk1 and PAM

Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06032, USA.
Molecular Endocrinology (Impact Factor: 4.02). 08/2010; 24(8):1543-58. DOI: 10.1210/me.2009-0381
Source: PubMed


Neurons and endocrine cells package peptides in secretory granules (large dense-core vesicles) for storage and stimulated release. Studies of peptidylglycine alpha-amidating monooxygenase (PAM), an essential secretory granule membrane enzyme, revealed a pathway that can relay information from secretory granules to the nucleus, resulting in alterations in gene expression. The cytosolic domain (CD) of PAM, a type 1 membrane enzyme essential for the production of amidated peptides, is basally phosphorylated by U2AF homology motif kinase 1 (Uhmk1) and other Ser/Thr kinases. Proopiomelanocortin processing in AtT-20 corticotrope tumor cells was increased when Uhmk1 expression was reduced. Uhmk1 was concentrated in the nucleus, but cycled rapidly between nucleus and cytosol. Endoproteolytic cleavage of PAM releases a soluble CD fragment that localizes to the nucleus. Localization of PAM-CD to the nucleus was decreased when PAM-CD with phosphomimetic mutations was examined and when active Uhmk1 was simultaneously overexpressed. Membrane-tethering Uhmk1 did not eliminate its ability to exclude PAM-CD from the nucleus, suggesting that cytosolic Uhmk1 could cause this response. Microarray analysis demonstrated the ability of PAM to increase expression of a small subset of genes, including aquaporin 1 (Aqp1) in AtT-20 cells. Aqp1 mRNA levels were higher in wild-type mice than in mice heterozygous for PAM, indicating that a similar relationship occurs in vivo. Expression of PAM-CD also increased Aqp1 levels whereas expression of Uhmk1 diminished Aqp1 expression. The outlines of a pathway that ties secretory granule metabolism to the transcriptome are thus apparent.

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    • "AQP1 has been found in DCVs in pituitary, chromaffin granules from adrenal medulla and pancreatic zymogen granules, while AQP5 has been found in parotid gland DCVs (Cho et al., 2002; Arnaoutova et al., 2008; Francone et al., 2010). AQP1 has also been found in the TGN (Francone et al., 2010). Its function in TGN and granules is to remove water to facilitate condensation of aggregated DCV proteins at the TGN and during DCV maturation. "
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