Processing and intracellular targeting of prosomatostatin-derived peptides: the role of mammalian endoproteases.
Prosomatostatin is cleaved at dibasic and monobasic sites to produce somatostatin-14 and somatostatin-28 respectively. The mammalian pro-protein convertases comprising furin, PACE4 and PC1-6 have recently been identified and are believed to mediate endoproteolysis of prohormone precursors such as prosomatostatin. Furin is membrane bound, localized to the Golgi and mediates constitutive processing. PC1 and PC2 are soluble and are expressed solely in endocrine and neuroendocrine tissues suggesting a key role in prohormone processing. We have investigated the endogenous and heterologous synthesis and processing of rat prosomatostatin in 1027B2 rat islet somatostatinoma cells and in constitutive (COS-7, PC-12) and regulated (AtT-20, GH3/GH4C1) secretory cells. We have correlated processing efficiency with: secretion through the constitutive or regulated pathways; endogenous expression of furin, PC1 and PC2; and expression or overexpression of furin, PC1 and PC2. Pulse-chase studies showed that prosomatostatin is rapidly and independently processed to somatostatin-14 and somatostatin-28. Furin is capable of monobasic processing of prosomatostatin and is a candidate somatostatin-28 convertase. PC1 and PC2 both effect dibasic processing of prosomatostatin and qualify as putative somatostatin-14 convertases. PC1 is active in constitutive and regulated secretory cells, has a broader specificity and is overall more potent than PC2. Efficient processing of prosomatostatin begins in a Golgi or pre Golgi compartment. It requires the milieu of the secretory cell but not the secretory granule.
Patel
Y C
YC
Fraser Laboratories, Department of Medicine, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada.
Galanopoulou
A
A
D000818:Animals; D001692:Biological Transport; D002451:Cell Compartmentation; D010450:Endopeptidases / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D013004:Somatostatin / Q000096:biosynthesis / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D011498:Protein Precursors; D013004:Somatostatin; C028456:prosomatostatin; D010450:Endopeptidases